bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2026–05–17
79 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Advances in adoptive cell therapy for ovarian cancer.
  2. Tumor-microenvironment-modulating microspheres to augment tumor-infiltrating lymphocyte therapy against solid tumors.
  3. [Tumor-infiltrating lymphocyte preparations have been in the fight against cancer for 40 years].
  4. Targeting intratumoral heterogeneity in pancreatic cancer with sequential TIL infusions.
  5. Multiple autologous tumor-infiltrating lymphocyte (LM103 infusion) therapy combined with immune checkpoint inhibitor induces repeated tumor regression in a patient with aggressive mucosal melanoma: a case report and literature review.
  6. Functional cytokine-based classification of tumor-infiltrating lymphocytes in melanoma.
  7. Association of CXCR7 and CXCR4 expression with tumor immune phenotypes in tubo-ovarian high-grade serous carcinoma.
  8. Analysis of computational tumor-infiltrating lymphocytes in breast cancer from the results of the TIGER challenge.
  9. AI-powered and manual assessment of tumor-infiltrating lymphocytes in early HER2-positive breast cancer in NSABP B-41.
  10. Tumor-Infiltrating Natural Killer Cell Characterization in Pancreatic Ductal Adenocarcinoma.
  11. Cardiolipin Induces CXCL9/CXCL10 Expression in Tumor-Infiltrating Lymphocytes.
  12. Severe Cryptosporidiosis Following Tumor-Infiltrating Lymphocyte Therapy in a Patient With Metastatic Mucosal Melanoma.
  13. Analysis of tumor-infiltrating lymphocytes as prognostic factor in triple-negative breast cancer: A protocol of systematic review and meta-analysis.
  14. The prognostic significance of the IASLC grading system in ALK-positive invasive non-mucinous adenocarcinoma of the lung: correlation with clinicopathological features.
  15. Tumor immune microenvironment reconstitution in patient-derived organoids enables therapy modeling for NSCLC.
  16. Predicting response to neoadjuvant therapy in breast cancer using longitudinal DCE-MRI deep learning integrated with tumor microenvironment data.
  17. A predictive 14-gene signature and FLI1 inhibition overcome tumor-infiltrating lymphocyte dysfunction in triple-negative breast cancer.
  18. In-house manufacture of plasma-derived human AB serum for use in cellular therapeutics.
  19. Refining the Multivariable Predictive-Prognostic PREDICTR-OPC Model for Survival in Surgical Escalation for Oropharyngeal Squamous Cell Carcinoma.
  20. IL-12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer.
  21. E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer.
  22. Advances in Immunotherapy for Head and Neck Squamous Cell Carcinoma: Focus on PD-1/PD-L1 Blockade and Beyond.
  23. Immune-remodeling mRNAs expressing IRF8 or NIK generate durable antitumor immunity in multiple cancer models.
  24. Lifileucel: Shedding Light on a New Treatment for Advanced Melanoma.
  25. The exploration of iparomlimab and tuvonralimab combined with de-escalated chemotherapy as an innovative neoadjuvant treatment strategy for locally advanced cervical cancer: a case report from the NICE-CC trial.
  26. The Role of Tumour-Infiltrating Lymphocytes in the Immune Microenvironment of Lymphoma and Their Immunotherapeutic Potential.
  27. Soluble Uric Acid Drives CD8⁺ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation.
  28. Cyclic mechanical stretch suppresses intrinsic apoptosis in high metastatic melanoma.
  29. Author Correction: Postprandial lipid metabolism durably enhances T cell immunity.
  30. NDRG3 is essential for sustaining antigen-driven T cell responses by protecting against restimulation-induced cell death.
  31. IL-15 and IL-21 synergy improves anti-tumor efficacy of iPSC-derived cytotoxic T cells in solid tumors.
  32. Protocol for a multi-modal performance-profiling workflow of CAR T cell products.
  33. Advanced Evaluation of T-Cell-Dependent Bispecific Antibodies Using Fluorescence Imaging and In Vivo Models.
  34. PRECISE-seq reveals disease-relevant TCR repertoires with phenotypic plasticity.
  35. Constructing a prognostic model for patients over 70 years of age with unoperated non-small cell lung cancer: A LASSO regression method.
  36. Immune microenvironment and strategy of immunotherapy in acral melanoma.
  37. Head-to-head comparison of nuclear imaging approaches to quantify tumor CD8+ T-cell infiltration.
  38. Targeting regulatory T cells in gastrointestinal cancers: current status and future perspectives.
  39. Upregulation of ADAM10 reinforces CD8+ T cells toward exhaustion in the TME.
  40. Tumor-Infiltrating mregDCs Restrain Anti-Tumor Immunity in Early Relapse HCC.
  41. Pulsed photobiomodulation reprograms the tumor immune microenvironment to restore local T cell-mediated antitumor immunity.
  42. Combined targeting of VISTA and sorafenib activates T cell-mediated anti-tumor immunity via the NF-κB/TNF axis in hepatocellular carcinoma.
  43. Extracellular vesicles as signal hubs and targeted platforms in hepatocellular carcinoma immunotherapy.
  44. Rapid identification of antigen-specific TCRs for cancer immunotherapy.
  45. Patient-Derived Organoid Modeling of Glypican-3 CAR-T Responses in Hepatocellular Carcinoma.
  46. Arid3b suppresses CD8 + T cell infiltration and function in microsatellite-stable colorectal cancer via Runx3.
  47. In Vivo Generation of CAR-T Cells: Current Obstacles, Strategic Solutions, and Clinical Translation.
  48. First-In-Human Trial of Encapsulated Cells Constitutively Expressing Localized IL-2 in Patients with High-Grade Serous Ovarian Carcinoma.
  49. Multi-omics profiling reveals tumor microenvironment characteristics linked to immunotherapy response and prognosis in non-small cell lung cancer.
  50. Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss.
  51. Prediction of lymphocyte-predominant breast cancer using microRNA expression in cytology specimens.
  52. Stable global repertoire architecture masks short-term clonal remodeling in intratumoral TCR repertoires.
  53. Early FMISO PET changes as exploratory predictors of immune checkpoint inhibitor response in advanced lung cancer: a pilot study.
  54. Vi må være mer kritiske til temperaturmålinger.
  55. Tumor-Derived Exosomal Fatty Acids Reprogram Neutrophils to Drive Neutrophil Extracellular Traps Formation and Lung Cancer Progression.
  56. LI-RADS TRA v2024 succeeds where RECIST and mRECIST fail: viability-based survival prediction in TACE-treated hepatocellular carcinoma.
  57. Eosinophils in lung cancer: from inflammatory cytokines to immunotherapeutic biomarkers.
  58. Estimation of accumulated dose to organs at risk in head and neck cancer patients treated with scheduled replanning and dose painting in the ARTFORCE trial.
  59. A Three-Gene Interferon Signature Predicts Sustained Complete Remission in Pediatric AML Patients.
  60. SHP1 expression in tumor-associated dendritic cells drives immunoevasion via impairing CD8+ memory T cell responses.
  61. Spatial Proximity Between PD-L1(+) Tumor-Associated Macrophages and CD8(+) T Cells Influences Response to Atezolizumab Plus Bevacizumab in Hepatocellular Carcinoma.
  62. Reinvigorating the Cancer-Immunity Cycle With Combined Oncolytic Virus and CAR-T Cell Therapies in Solid Tumors.
  63. Selecting Representative Tumour Bed Slices May Allow Reduced Embedding Without Loss of Accuracy in Response Evaluation to Neoadjuvant Immunotherapy in Stage IIIB/C Cutaneous Melanoma.
  64. PRDM1 Is Associated with Chemoradiotherapy-Associated Enrichment of Adaptive NK Cells in Cervical Cancer.
  65. CD8+ T cells turn resilient under stress.
  66. Exploring the Immune Microenvironment for Predicting Immunotherapy Efficacy in Epstein-Barr Virus-Associated Gastric Cancer.
  67. Injectable and viscoelastic click alginate hydrogels for spatio-temporal T cell administration in vivo.
  68. T-Cell Exhaustion in the Tumor Microenvironment: Subcellular Dysfunction, Pan-Cancer Characteristics, and Therapeutic Interventions.
  69. Allogenic Memory-Like Natural Killer Cell Therapy.
  70. Translational potential of γδ T cells in hematologic diseases: from immunobiology to therapeutic innovation.
  71. Clinical utility and prognostic value of GATA3 in epithelioid malignant mesothelioma: a practical and cost-effective approach for resource-limited settings.
  72. Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway.
  73. Single-nucleus sequencing dissects the malignant change of early lung adenocarcinoma: SMAD3 suppresses antitumor T cell immunity via ICAM1.
  74. Characterization of Patients with Unresectable Hepatocellular Carcinoma in REFLECT Who Achieved Tumor Response or Alpha-Fetoprotein Response When Treated with Lenvatinib.
  75. A role for CD8+ T cells in lupus nephritis.
  76. Vδ1 T cells exhibit high lactic acid resistance and antitumor activity in solid tumors.
  77. Immune-metabolic profiling of triple-negative breast cancer during neoadjuvant chemotherapy.
  78. Ten years of clinical genetic therapies for sickle cell disease: Current and future directions.
  79. MEOX1 Coordinates Autocrine-Paracrine Programs via SPHK1/S1P to Promote Lymph Node Metastasis in Ovarian Cancer.
  1. Front Immunol. 2026 ;17 1794716
    Advances in adoptive cell therapy for ovarian cancer.
    Na Zhao, Yujiao An, Shanwei Guo, Zhen Xu, Hongtang Shi, Zhentao Zhang.
      Ovarian cancer remains the most lethal gynecological malignancy worldwide, with late-stage diagnosis, high recurrence rates, and chemoresistance posing persistent clinical challenges. Adoptive cell therapy (ACT), a rapidly advancing immunotherapeutic strategy, offers promising efficacy with low systemic toxicity and has emerged as a compelling option to address these limitations. This review provides a comprehensive overview of ACT modalities-including tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor T cells (CAR-T), natural killer (NK) cells, and other emerging cellular therapies such as TCR-T, cytokine-induced killer (CIK) cells, and γδ T cells-in the context of ovarian cancer. We highlight the mechanistic underpinnings of ACT, the immunosuppressive features of the ovarian tumor microenvironment, and cutting-edge advances in combinatorial regimens, genetic engineering, and cell design aimed at overcoming therapeutic resistance. In particular, we discuss antigen specificity, tumor immune evasion, and stromal barriers, and summarize current clinical trial progress, efficacy outcomes, and translational barriers. Together, these insights underscore the transformative potential of ACT in ovarian cancer and outline future directions for personalized and scalable immunotherapies.
    Keywords:  adoptive cell therapy; chimeric antigen receptor T cells; immunosuppression; ovarian cancer; tumor immune microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1794716
  2. Cell Rep Med. 2026 May 08. pii: S2666-3791(26)00211-9. [Epub ahead of print] 102794
    Tumor-microenvironment-modulating microspheres to augment tumor-infiltrating lymphocyte therapy against solid tumors.
    Mingkang Li, Shen Yan, Xiaoying Yan, Ziwei Nie, Haihan Wang, Qiaofeng Li, Haoqi Liu, Wenzhuo Yu, Shuai Zhang, Yanbin Liu, Hong Chen, Winston Duo Wu, Yu Chao, Zhuang Liu.
      Tumor-infiltrating lymphocyte (TIL) therapy is a T cell therapy approved for treating solid tumors. However, the dense extracellular matrix (ECM) and immunosuppressive tumor microenvironment (TME) result in limited numbers and activities of initially harvested TILs, further leading to time-consuming preparation processes and suboptimal treatment efficacy. Herein, we develop alginate-based hydrogel microspheres co-loaded with hyaluronidase (HAase) and chemokine CXCL9. With released HAase to degrade the extracellular matrix and CXCL9 to recruit lymphocyte infiltration, such microspheres after intratumoral injection allow effective TME modulation, leading to greatly enhanced TIL numbers in tumors. TILs collected from those pre-treated tumors exhibit not only accelerated ex vivo expansion but also markedly improved activities and anti-exhaustion capacities. Those TILs after re-infusion could significantly inhibit tumor growths and metastases in different tumor models. Our work demonstrates that modulating TME before tumor collection may be an effective and clinically practical approach to boost current TIL therapies.
    Keywords:  T cell exhaustion; T cell infiltration; TILs; TME; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102794
  3. Orv Hetil. 2026 May 10. 167(19): 740-745
    [Tumor-infiltrating lymphocyte preparations have been in the fight against cancer for 40 years].
    Sámuel Balázs.
      This review article summarizes the development of tumor-infiltrating lymphocyte (TIL) based immunotherapy, from the pioneering work of Rosenberg, Spiess and Lafreniere to the 2024 regulatory approval of lifileucel, the first cell therapy authorized for the treatment of solid tumors. A key advantage of TIL therapy over the chimeric antigen receptor (CAR) T-cell technology is its polyclonal T-cell receptor repertoire, which enables more effective recognition of heterogeneous tumor cell populations. The therapeutic approach is based on the ex vivo expansion and activation of lymphocytes isolated from a patient's own tumor, followed by their reinfusion after lymphodepleting conditioning. The review details the major technological advances in the field, with particular emphasis on the significance of "young TIL" protocols, which preserve proliferative capacity and prevent terminal differentiation by shortening culture duration. Current challenges are also discussed, including the need for more precise selection of tumor-reactive T cells, improved tumor homing and infiltration, and reduction of treatment-associated systemic toxicities. Next-generation strategies, including modified cytokines and genetically engineered TILs, aim to replace high-dose IL-2 and intensive chemotherapy, thereby reducing side effects. Overall, the approval of lifileucel validates the clinical relevance of TIL therapy. Fine-tuning the technology through standardized manufacturing and modulation of the tumor microenvironment promises to expand its application to other solid malignancies, fundamentally reshaping cancer treatment. By addressing the limitations of earlier methods, modern TIL therapy serves not as a final solution, but as a transitional foundation for more precise and controllable cellular immunotherapies. Orv Hetil. 2026; 167(19): 740-745.
    Keywords:  adoptive cell therapy; adoptív sejtterápia; immunotherapy; immunterápia; tumor-infiltrating lymphocytes; tumorinfiltráló lymphocyták
    DOI:  https://doi.org/10.1556/650.2026.33557
  4. Cytotherapy. 2026 Mar 04. pii: S1465-3249(26)00102-7. [Epub ahead of print]28(7): 102141
    Targeting intratumoral heterogeneity in pancreatic cancer with sequential TIL infusions.
    Lucas C M Arruda, Julia Karbach, Dragan Kiselicki, Evgueni Sinelnikov, Dirk Gustavus, Hans Hoffmeister, Akin Atmaca, Elke Jäger.
      Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is effective in melanoma and selected solid tumors, but its potential in pancreatic ductal adenocarcinoma (PDAC) remains largely unexplored. We report a 39-year-old male with metastatic PDAC involving lung, peritoneal, liver, and lymph node who received three sequential infusions of TIL expanded ex vivo with IL-2/IL-15/IL-21 from a lung metastasis. Each infusion followed low-dose lymphodepletion and IL-2 support. The patient achieved stable disease after the first infusion and a partial response after the second along with reductions in serum CA19-9. Genome sequencing revealed substantial inter-tumoral heterogeneity, with mutations in ITGB2, C1QTNF3, CDK9, TMEM200C, FHOD1 and ZZZ3 impacting TIL infiltration and clinical response. RNA-seq showed that responding lesions were enriched for inflammatory and tumor-specific programs, displayed enrichment of T-cell activation transcripts and had reduced infiltration of cancer-associated fibroblasts. TCR sequencing confirmed the robust infiltration of TIL-derived CD8+ clonotypes, while functional assays demonstrated a polyclonal recognition of patient-derived somatic mutations and cytotoxicity against autologous tumor lines. Single-cell TCR mapping further validated the dominance of tumor-specific CD8+ clonotypes in responding lesions. This case demonstrates the feasibility and immunological activity of TIL therapy in PDAC, while underscoring the impact of spatial tumor heterogeneity on therapeutic outcomes.
    Keywords:  IL-15; IL-2; IL-21; cytotoxic T-cells; pancreatic ductal adenocarcinoma; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102141
  5. Front Oncol. 2026 ;16 1789442
    Multiple autologous tumor-infiltrating lymphocyte (LM103 infusion) therapy combined with immune checkpoint inhibitor induces repeated tumor regression in a patient with aggressive mucosal melanoma: a case report and literature review.
    Fenge Li, Yue Xu, Yupeng Wang, Ning Mu, Mei Liu, Weihong Feng, Yongming Xue, Shengnan Wu, Xinyi Wang, Gregory Lizee, Chunhua Ma.
      Tumor-infiltrating lymphocyte (TIL) therapy was approved as a one-dose treatment indicated for melanoma patients who have progressed on anti-PD-1 therapy. However, the majority of patients show only short-duration responses, highlighting the urgent need to explore multiple cycles of TIL therapy and combination strategies. We report a case of a patient with aggressive stage IV nasal mucosal malignant melanoma with disease progression on multiple lines of immunotherapy who was enrolled in a clinical trial evaluating the safety and efficacy of autologous TIL therapy. Prior to TIL infusion, the patient underwent lymphodepletion with cyclophosphamide followed by fludarabine for 5 days. Approximately 24 hours later, the patient received an intravenous infusion of autologous TIL, followed by high-dose interleukin-2 for 6 days to support T-cell expansion and persistence. The patient achieved a partial response (PR) at 6 weeks and a complete response (CR) at 12 weeks post-infusion. However, tumor relapse occurred 7 months later. The patient then received a second TIL infusion, resulting in stable disease (SD) with transient shrinkage, but rapid regrowth occurred within 3 weeks. The patient subsequently received a third TIL infusion and achieved another PR within 2 weeks. Manageable adverse events were observed and resolved shortly after TIL treatments. A time-course study of peripheral blood cell subtyping and cytokine secretion demonstrated a long-term immune response. Longitudinal immune monitoring revealed sustained systemic immune activation. This case report shows that multiple autologous TIL therapies can induce repeated clinical and immunological responses in a heavily anti-PD-1-pretreated patient with advanced melanoma, underscoring the feasibility and therapeutic potential of multiple TIL treatments. Clinical trial registration:https://clinicaltrials.gov, identifier NCT06697665, NCT05941936, NCT05971589.
    Keywords:  clinical response; cytokine secretion; immune monitoring; multiple TIL therapy; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fonc.2026.1789442
  6. Sci Rep. 2026 May 14.
    Functional cytokine-based classification of tumor-infiltrating lymphocytes in melanoma.
    Meshack Bida, Rodney Hull, Thabiso Victor Miya, Tebogo Marutha, Zodwa Dlamini.
      Tumor-infiltrating lymphocytes (TILs) are important prognostic and predictive biomarkers of melanoma. However, the histological classification of TILs into brisk, non-brisk, or absent categories remains subjective and prone to inter-observer variability. The tumor immune microenvironment (TIME), regulated by cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), plays a central role in tumor progression and therapeutic response. This study investigated whether cytokine immune scoring could serve as a functional adjunct to histological TIL evaluation. A total of 205 early-stage nodular cutaneous melanoma cases from treatment naïve black South African patients were analyzed (65 brisk, 60 non-brisk, and 80 absent). TNF-α and IFN-γ expression were quantified by immunohistochemistry using a modified Allred method and correlated with TIL categories. Three experienced pathologists took part in cytokine immune scoring and any discrepancies were addressed by consensus. Both cytokines were significantly associated with TIL patterns (χ² p < 0.001, Cramér's V ≈ 0.31-0.41), with expression increasing from absent to non-brisk to brisk TILs. Logistic regression revealed 3-4-fold higher odds of high cytokine expression in non-brisk and 6-8-fold higher odds in brisk versus absent cases. The diagnostic metrics indicated moderate sensitivity and specificity but strong negative predictive values. Discordant cases revealed immune activity that was not reflected by morphology alone. These findings support cytokine immune scoring as a complementary tool for refining the functional assessment of the TIME in melanoma.
    Keywords:  Cytokine immune scoring; IFN-gamma; Melanoma; TNF-alpha; Tumor immune microenvironment; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1038/s41598-026-50196-9
  7. Ir J Med Sci. 2026 May 13.
    Association of CXCR7 and CXCR4 expression with tumor immune phenotypes in tubo-ovarian high-grade serous carcinoma.
    Burak Tatar, Sultan Caliskan, Fatma Nur Uygun, Sercan Ergün, Neslihan Hekim, Mehmet Kefeli, Sezgin Gunes.
       BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are associated with favorable outcomes in high-grade serous ovarian carcinoma (HGSC); however, the tumor microenvironment may modulate immune cell infiltration. This study aimed to evaluate the association between tumor and stromal expression of CXCL12, tumor expression of CXCR4 and CXCR7, immune phenotypes, and survival outcomes in tubo-ovarian HGSC.
    METHODS: Eighty-six patients with primary tubo-ovarian HGSC who underwent cytoreductive surgery were retrospectively analyzed. Immunohistochemical expression of CXCL12 (tumor and stroma), CXCR4, and CXCR7 was assessed. TILs were semi-quantitatively scored and dichotomized as low (score 1) or high (scores 2-3). Immune phenotypes were classified as immunogenic, immune-excluded, or immune-ignorant. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods, log-rank tests, and Cox regression. Multivariable logistic regression was used to identify factors associated with high TILs.
    RESULTS: Median RFS was 23.2 months (95% CI, 19.2-27.1) and median OS was 47.3 months (95% CI, 36.3-55.0). RFS differed significantly across immune phenotypes (log-rank p=0.047), with shorter RFS observed in the immune-excluded phenotype compared with the immunogenic phenotype (hazard ratio, 2.20; 95% CI, 1.14-4.25). High tumor CXCR7 expression was independently associated with a lower likelihood of high TILs (adjusted odds ratio, 0.22; 95% CI, 0.07-0.65). CXCL12 expression was not associated with survival outcomes.
    CONCLUSION: Tumor CXCR7 expression is associated with reduced lymphocytic infiltration and an immune-excluded phenotype in HGSC, suggesting a potential role of the CXCR7 axis in shaping the tumor immune microenvironment.
    Keywords:  CXCL12; CXCR4; CXCR7; Immune exclusion; Tubo-ovarian high-grade serous carcinoma; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s11845-026-04437-5
  8. Nat Commun. 2026 May 15.
    Analysis of computational tumor-infiltrating lymphocytes in breast cancer from the results of the TIGER challenge.
    TIGER consortium
      Tumor-infiltrating lymphocytes (TILs) is a recognized prognostic biomarker in breast cancer. However, poor interobserver agreement and limited reproducibility highlight the need for computational approaches. Despite advances, adoption of computational models has been hindered by lack of standardized methods and robust benchmarks. To address this, we launched TIGER, an international competition to build open-source computational TILs (cTILs) models. Here, we present a multi-centric analysis of cTILs methods on resections and biopsies from 3,708 human epidermal growth factor receptor 2-positive (HER2+) or triple-negative breast cancers (TNBC) from clinical practice and phase 3 trials. We report benchmarks on image analysis performance, show strong agreement of cTILs with pathologists, and demonstrate positive association of cTILs with neoadjuvant therapy response in HER2+, superior to visually scored TILs. We also show that cTILs add independent prognostic information to clinical variables in TNBC resections. Data, methods and benchmarks are publicly available: https://tiger.grand-challenge.org/.
    DOI:  https://doi.org/10.1038/s41467-026-72956-x
  9. NPJ Breast Cancer. 2026 May 14.
    AI-powered and manual assessment of tumor-infiltrating lymphocytes in early HER2-positive breast cancer in NSABP B-41.
    Ilana Schlam, Gong Tang, Khalid AbdulJabbar, Haixi Yan, Xuelin Gu, Tanner J Freeman, Sai Maley, Brent T Harris, Priya Rastogi, Isaac Hook, Norman Wolmark, Roberto Salgado, Sandra M Swain.
      The assessment of tumor-infiltrating lymphocyte (TILs), together with gene expression signatures (GES), has the potential to guide personalized breast cancer therapy. We included 262 patients from the phase III NSABP B-41 trial, which evaluated neoadjuvant HER2-targeted therapies in combination with chemotherapy. We conducted a manual and artificial intelligence (AI)-based analyses of TILs, as well as GES from RNA sequencing. Higher manual TILs as a continuous variable were associated with pathologic complete response (pCR) in patients with estrogen receptor (ER)-negative disease. AI-based TILs were associated with pCR regardless of ER status. Immune GES (iGES) were associated with pCR. Manual TILs were not associated with event-free survival (EFS), while AI-TIL showed a marginal association. These results support the use of TIL assessment, complemented by GES, as a prognostic biomarker in HER2-positive breast cancer. Future studies are needed to evaluate their predictive utility to guide treatment decisions.
    DOI:  https://doi.org/10.1038/s41523-026-00961-w
  10. Cells. 2026 Apr 28. pii: 797. [Epub ahead of print]15(9):
    Tumor-Infiltrating Natural Killer Cell Characterization in Pancreatic Ductal Adenocarcinoma.
    Andreia Maia, Hasti Calá, Eric de Sousa, Joana R Lérias, Carolina M Gorgulho, Patrícia A António, Jéssica Kamiki, Dário Ligeiro, Luis M Borrego, Markus Maeurer, Mireia Castillo-Martin.
      Pancreatic ductal adenocarcinoma (PDAC) has high mortality rates, poor prognosis, and currently limited effective treatments. Natural killer (NK) cells from tumor-infiltrating lymphocytes (TIL) show promise for cancer treatment due to their ability to migrate to the tumor microenvironment (TME) and safe profile. However, expanding functional patient-derived NK cells remains challenging. Here, we cultured, expanded, and characterized TIL-NK cells isolated from central and peripheral tumor regions from PDAC. Ex vivo patient-derived PBMCs and TIL were cultured under IL-2, IL-15, and IL-12 stimulation. Phenotypical and functional NK cell characterization was assessed at the time of surgery and after 12 days of culture evaluating immunophenotype, expansion rate, and activation. A distinct distribution of NK cell infiltration was observed within the TME, with higher NK cell numbers in the periphery of the tumor compared to the central area. Most NK cells displayed a cytotoxic phenotype (CD56+ CD16+). Compared to PBMCs, TIL-NK cells expressed lower activation markers but superior tumor infiltration and expansion rates, particularly those isolated from the central regions. Notably, cytokine stimulation improved patient-derived NK cell activation and cytotoxic profile. This pilot study provides preliminary but critical insights regarding TIL-NK cells from PDAC patients, laying groundwork for developing NK cell-based immunotherapies for solid tumors.
    Keywords:  NK-TIL; TIL therapy; adoptive cell therapy; natural killer cells; pancreatic ductal adenocarcinoma; solid tumours; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/cells15090797
  11. Cells. 2026 Apr 28. pii: 798. [Epub ahead of print]15(9):
    Cardiolipin Induces CXCL9/CXCL10 Expression in Tumor-Infiltrating Lymphocytes.
    Joana R Lérias, Eric de Sousa, Carolina M Gorgulho, Jéssica Kamiki, Patrícia A António, Rodrigo Eduardo, Matilde Sedas, Nuno Figueiredo, Jian Han, Soon Seog Jeong, Ridong Chen, Markus J Maeurer.
      Background: Cardiolipin (CL) is a phospholipid composed of a glycerol linked with two phosphatidate moieties that constitutes an integral part of the human inner mitochondrial membrane under physiological conditions. It is also vital for bacterial membrane transport and key bacterial functions associated with cell division and infection. CL is released in the cytosol or into the extracellular milieu upon cell death and during inflammation. We therefore tested the ability of CL to activate and expand tumor infiltrating lymphocytes (TIL) from patients with epithelial cancer. Methods: TIL were isolated from gastrointestinal tumor tissues and expanded in vitro in the presence of CL. The role of the NLRP3 inflammasome was evaluated using the specific inhibitor MCC950 and siRNA-mediated silencing of NLRP3. Phenotypic changes and T-cell potency were assessed via CXCL9/10 expression levels. To characterize the immune repertoire, deep TCR sequencing was performed to compare the TCR Vα and Vβ CDR3 regions between TIL and the corresponding tumor tissue. Recognition of autologous tumor cells and tumor-specific mutations, including mutations in KRAS and mitochondrial UQCRFS1 (D145V), was assessed using MHC class I and II restriction assays. Results: CL-expanded TIL exhibited increased CXCL9/10 expression, which is associated with increased potency of tissue invasion. CL-TIL exhibited broader recognition of frequently occurring KRAS mutations, and this effect could be blocked with an inhibitor (MCC950) of the NLRP3 pathway, a multiprotein inflammatory complex associated with danger signaling. TIL exhibited an enriched TCR Vα and Vβ CDR3 repertoire compared to tumor tissue, as defined by deep TCR sequencing. TCR αβ+ TIL recognized autologous tumor tissue in an MHC class I- and class II-restricted fashion, including the mutant HLA-DP-restricted mitochondrial protein associated with the electron respiratory chain complex III (UQCRFS1 D145V) presented by autologous tumor cells. Conclusions: CL activates the NLRP3 inflammasome pathway in TIL from patients with GI cancer and increases CXCL9/CXCL10 expression in TIL, resulting in enhanced recognition of mutant cancer-associated target epitopes, including a mitochondrial protein. CL may provide a danger signal: that facilitates TIL expansion via CL-activated pathways.
    Keywords:  T-cell receptor (TCR); cardiolipin; cytokines; gastrointestinal cancer; mitochondria; mutant mitochondria; pancreatic cancer; peptide recognition; tumor-associated antigen (TAA); tumor-infiltrating lymphocytes (TIL)
    DOI:  https://doi.org/10.3390/cells15090798
  12. ACG Case Rep J. 2026 May;13(5): e02113
    Severe Cryptosporidiosis Following Tumor-Infiltrating Lymphocyte Therapy in a Patient With Metastatic Mucosal Melanoma.
    Gagandeep Gill, Omar Saab, Kartik Patel, Achyut K Bhattacharyya, Diane Roden, Avin Aggarwal.
      Cryptosporidium is a protozoan parasite that can cause respiratory and gastrointestinal illnesses with watery diarrhea. Severe disease may occur in immunocompromised patients, especially those with acquired immunodeficiency syndrome or metastatic mucosal melanoma on immunosuppressive therapy. We report a 72-year-old man with metastatic mucosal melanoma treated with surgery, radiation, and tumor-infiltrating lymphocytes therapy complicated by hemophagocytic lymphohistiocytosis and autoimmune colitis. He presented with an acute profuse diarrhea despite sulfasalazine and budesonide therapy for his colitis. Intestinal biopsy confirmed Cryptosporidium parvum. Although uncommon, cryptosporidial infection should be suspected in immunocompromised patients with persistent diarrhea. Diagnosis is via stool microscopy, polymerase chain reaction, or enzyme immunoassay.
    Keywords:  case report; cryptosporidiosis; gastroenterology; literature review; metastatic mucosal melanoma; tumor-infiltrating lymphocyte therapy
    DOI:  https://doi.org/10.14309/crj.0000000000002113
  13. PLoS One. 2026 ;21(5): e0342085
    Analysis of tumor-infiltrating lymphocytes as prognostic factor in triple-negative breast cancer: A protocol of systematic review and meta-analysis.
    Luciana Carla Martins de Aquino, Elisandra Inara Silva Andrade, Luana Maria Ferreira Nunes, Edilmar de Moura Santos, Ayane Cristine Alves Sarmento, Kleyton Santos de Medeiros, Ana Katherine Gonçalves.
       PURPOSE: Breast cancer is the most common malignant tumor among women worldwide, with an estimated 2.3 million new cases and nearly 670,000 deaths reported in 2022. The absence of hormone receptors and HER2 in triple-negative breast cancer (TNBC) reduces therapeutic options, contributing to a poorer prognosis. Tumor-infiltrating lymphocytes (TILs) are cells present in the tumor microenvironment, associated with a better prognosis and potentially playing a role in patient stratification and therapeutic management in the future. This protocol aims to assess the prognostic value of TILs in the survival of patients with TNBC, as well as their relationship with disease recurrence.
    METHODS: Comprehensive search will be conducted in the following databases: PubMed, Embase, Lilacs, Web of Science, Scopus, SciELO, ScienceDirect, and the Cochrane Library. The search will include cohort, case-control, and clinical trials studies that approach the prognostic value of TILs in TNBC and their role in optimizing treatment strategies, and no language restrictions. Two independent reviewers will select articles based on predefined inclusion and exclusion criteria, extract data, and assess the risk of bias using the QUIPS tool. Data synthesis will be conducted using the "meta" package in R software, version 4.3.1.
    CONCLUSIONS: This systematic review will synthesize current evidence on the prognostic significance of TILs in triple-negative breast cancer and their association with patient survival and disease recurrence. The findings may contribute to a better understanding of TILs as potential biomarkers for prognosis and guide future therapeutic strategies in TNBC management. Review registration: CRD42024568600.
    DOI:  https://doi.org/10.1371/journal.pone.0342085
  14. J Pathol Clin Res. 2026 May;12(3): e70093
    The prognostic significance of the IASLC grading system in ALK-positive invasive non-mucinous adenocarcinoma of the lung: correlation with clinicopathological features.
    Dongmei Gu, Jie Bao, Hong Chen, Siyi Chen, Chenxi Shi, Xia Guo, Xiaoyu Zhou, Zhe Lei, Lingchuan Guo, Qianqian Yang.
      The prognostic value of the International Association for the Study of Lung Cancer (IASLC) grading system in anaplastic lymphoma kinase (ALK)-positive invasive non-mucinous adenocarcinoma (INMA) remains unclear, particularly in relation to the tumor immune microenvironment (TIME). This retrospective study included 108 patients with ALK-positive INMA. Tumors were graded according to the IASLC system. Clinicopathological features, progression-free survival (PFS), and overall survival (OS) were analyzed. Immunohistochemistry was used to assess PD-L1 expression and tumor-infiltrating lymphocytes (TILs), including CD4+, CD8+, and FoxP3+ regulatory T cells. Associations were evaluated using Kaplan-Meier analysis, Cox regression models, and correlation analyses. Higher IASLC grades were significantly associated with more aggressive pathological features, elevated PD-L1 expression, and shorter progression-free survival (PFS). Higher-grade tumors exhibited enhanced T-cell infiltration, predominantly driven by CD8+ T cells, while no significant difference in FoxP3+ Treg density was observed across grades. Notably, the CD4:CD8 ratio decreased, whereas the CD8:FoxP3 ratio increased with tumor grade, indicating a shift toward a CD8-dominant immune microenvironment. Importantly, this cytotoxic predominance occurred in parallel with elevated PD-L1 expression, suggesting an immune context consistent with adaptive immune resistance rather than effective anti-tumor immunity. The IASLC grading system effectively identifies a high-risk subgroup of ALK-positive INMA characterized by aggressive tumor behavior and a dynamically regulated immune microenvironment. High-grade tumors exhibit features of immune engagement coupled with checkpoint-mediated regulation, supporting a model of adaptive immune resistance. These findings underscore the necessity of combination therapeutic strategies that simultaneously target ALK and immune checkpoint modulation in high-grade INMA.
    Keywords:  International Association for the Study of Lung Cancer (IASLC); PD‐L1 expression; T lymphocyte; lung invasive non‐mucinous adenocarcinoma (INMA); prognostic stratification; the anaplastic lymphoma kinase (ALK)
    DOI:  https://doi.org/10.1002/2056-4538.70093
  15. Cell Rep Methods. 2026 May 13. pii: S2667-2375(26)00039-1. [Epub ahead of print] 101339
    Tumor immune microenvironment reconstitution in patient-derived organoids enables therapy modeling for NSCLC.
    Enrique Podaza, Jared Capuano, Hui-Hsuan Kuo, Majd Al Assaad, Geoffrey Markowitz, M Victoria Revuelta, John Nguyen, Adriana Irizarry, Hiranmayi Ravichandran, Sarah Ackermann, Troy Kane, Jyothi Manohar, Alyssa Duren-Lubanski, Michael Sigouros, Jenna Moyer, Bhavneet Bhinder, Pooja Chandra, Murtaza Malbari, Karsten Boehnke, Juan Miguel Mosquera, Vivek Mittal, Andrea Sboner, Hamza Gokozan, Nasser Altorki, Olivier Elemento, M Laura Martin.
      Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Despite various therapeutic options, treatment resistance is common, underscoring the need for effective combination therapies and reliable pre-clinical models for patient-specific evaluation. Here, we describe strategies for reconstituting tumor immune microenvironment (TIME) components within patient-derived tumor organoid (PDTO) cultures. We established a tumor processing pipeline that enables concurrent expansion of tumor-infiltrating lymphocytes (TILs) and PDTO generation from the same resection. We optimized scalable assays to assess IFN-γ secretion and T cell cytotoxicity with immune checkpoint inhibitors (alone or in combination) and targeted inhibitors, capturing inter-patient heterogeneity and intra-patient variations between TILs and peripheral blood mononuclear cells (PBMCs). Additionally, we developed methods for differentiating PDTO-specific tumor-associated macrophages (TAMs) and established PDTO-TAM co-culture systems to evaluate TAM effects on PDTO growth and chemotherapy sensitivity. All approaches are scalable to high-throughput levels, highlighting the value of TIME-PDTO co-cultures for therapeutic modeling and precision medicine.
    Keywords:  CP: cancer biology; CP: immunology; T cells; co-cultures; immunotherapy; tumor microenviroment; tumor organoids; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101339
  16. Front Immunol. 2026 ;17 1749668
    Predicting response to neoadjuvant therapy in breast cancer using longitudinal DCE-MRI deep learning integrated with tumor microenvironment data.
    Lan Yan, Xianming Huang, Lan Liu, Ao Wu, Yingyi Luo, Hao Li, Shaofeng Yi, Tenghua Yu, Qiao Zeng.
       Objective: This study developed and validated a multimodal fusion model to enable the early and accurate prediction of pathological complete response (pCR) to neoadjuvant therapy (NAT) in breast cancer. The model integrates deep learning (DL) features derived from longitudinal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) acquired early during treatment, peripheral blood inflammatory (PBI) indices, and baseline levels of tumor-infiltrating lymphocytes (TILs).
    Methods: A total of 262 breast cancer patients receiving NAT were retrospectively enrolled and divided into a training cohort (n=183) and a validation cohort (n=79) based on the time of surgery. Deep learning models (Pre-NAT DL and Post-2nd-NAT DL) were constructed using features extracted from pre-treatment (baseline) and post-second-cycle DCE-MRI images, respectively. An immune-inflammation model was built using baseline TILs and dynamically changing PBI indices. A clinical model was developed based on baseline clinicopathological characteristics. Finally, a combined model was constructed by integrating features from all the aforementioned modalities. The models were developed using various machine learning algorithms, and their predictive performance was assessed and compared.
    Results: In the validation cohort, the combined model achieved superior predictive performance, with an area under the receiver operating characteristic curve of 0.90 and specificity of 95%. Its performance was significantly better than that of any single-modality model. The Post-2nd-NAT DL model (AUC = 0.85) outperformed the Pre-NAT DL model (AUC = 0.75), confirming the critical predictive value of deep learning features from early-treatment DCE-MRI. The immune-inflammation model also exhibited independent predictive capability (AUC = 0.73).
    Conclusion: The combined model integrating deep learning features from early longitudinal DCE-MRI, dynamic systemic inflammatory indicators, and baseline TILs significantly enhances the early prediction of pCR to NAT in breast cancer. This multimodal fusion strategy offers a potential tool to aid personalized treatment planning in breast cancer patients undergoing NAT.
    Keywords:  breast cancer; deep learning; dynamic contrast-enhanced MRI; neoadjuvant therapy; pathological complete response; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1749668
  17. Biochem Biophys Res Commun. 2026 May 12. pii: S0006-291X(26)00697-2. [Epub ahead of print]823 153933
    A predictive 14-gene signature and FLI1 inhibition overcome tumor-infiltrating lymphocyte dysfunction in triple-negative breast cancer.
    Meng Jia, Longwei Jiang, Siqi Han, Ying Zhang, Juanjuan He, Guiyang He, Chong Wu, Heng Zhang, Hongwei Liang, Ke Zen, Xudong Ao, Shaochang Jia, Junqing Liang.
      Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Although immune checkpoint inhibitors such as pembrolizumab have improved clinical outcomes in a subset of patients, limited response rates and durability highlight the need for alternative strategies. Tumor-infiltrating lymphocyte (TIL)-based adoptive cell therapy represents a promising approach; however, the absence of reliable biomarkers for TIL functionality remains a major obstacle. In this study, we isolated TILs and autologous tumor cells from nine TNBC patients and classified TILs as reactive or non-reactive based on cytotoxic activity. Transcriptomic profiling combined with weighted gene co-expression network analysis and machine learning approaches identified a 14-gene signature that robustly distinguished reactive from non-reactive TILs. Transcription factor analysis revealed that Friend leukemia integration 1 (FLI1) regulates a large proportion of genes upregulated in non-reactive TILs. Notably, pharmacological inhibition of FLI1 using TK216 restored the cytotoxic function of non-reactive TILs and reduced expression of immunosuppressive genes. These findings identify a functional gene signature associated with TIL reactivity and suggest that targeting FLI1 may represent a strategy to enhance TIL-based immunotherapy in TNBC.
    Keywords:  Biomarkers; Breast cancer; FLI1; TK216; Tumor infiltrating lymphocyte
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153933
  18. Cytotherapy. 2026 Feb 18. pii: S1465-3249(26)00079-4. [Epub ahead of print]28(7): 102117
    In-house manufacture of plasma-derived human AB serum for use in cellular therapeutics.
    Paige O Mirsky, John Lister, Albert D Donnenberg.
      Successful manufacture of cellular therapeutic products requires a medium containing key nutrients to support cell expansion. Some of the most common supplements to cell culture media include serum products such as fetal bovine serum, human serum albumin, and human AB serum. Medium supplementation with human AB serum provides critical growth factors, lipids, proteins, and hormones without the risk of cross-species antigenicity or anti-AB antibodies. In this report, we describe the use of pooled defibrinated plasma, sourced from a US blood bank, to produce serum in-house that complies with blood product, cell therapy, and current Good Manufacturing Practice (cGMP) regulations. We are currently using this product as a culture supplement for the in-house manufacture of chimeric antigen receptor T cell (CAR-T) and tumor-infiltrating lymphocyte (TIL) therapeutics under IND. Our current validated clinical laboratory procedure is included as supplementary material.
    Keywords:  cGMP; cellular therapy; chimeric antigen receptor T cells; defibrination; human AB serum; human plasma; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102117
  19. Laryngoscope. 2026 May 12.
    Refining the Multivariable Predictive-Prognostic PREDICTR-OPC Model for Survival in Surgical Escalation for Oropharyngeal Squamous Cell Carcinoma.
    Lauren L Zhang, Caroline Kristunas, C Max Robinson, Jill M Brooks, Alice J Sitch, Stuart C Winter, Justin Weir, Paul Matthews, Terry M Jones, Keith Hunter, Pawel Golusinski, Ketan A Shah, Selvam Thavaraj, Catharine M West, Syed Haider, Edward Odell, Paul Nankivell, Sandra V von Zeidler, Hisham Mehanna.
       OBJECTIVES: The PREDICTR-OPC model is the only prognostic classifier for oropharyngeal squamous cell carcinoma (OPSCC) also predictive of surgical outcomes. Of the four biomarkers included, survivin contributes minimally and presents practical limitations. This study aimed to refine and simplify the model by removing survivin, then re-assess its prognostic predictive performance compared to the original.
    METHODS: This retrospective cohort study analyzed a multi-center training cohort (n = 600) and an external validation cohort (n = 385) of OPSCC patients. Tumor biopsies were stained for p16, high-risk human papillomavirus (HR-HPV) DNA, tumor-infiltrating lymphocytes (TILs), and survivin and independently scored by at least three certified pathologists. Cox proportional hazards models assessed overall survival (OS), comparing three-biomarker (p16, HR-HPV, TILs) and four-biomarker models. Hazard ratios (HRs) for OS were estimated in the validation cohort, adjusting for covariates. Discrimination, calibration, and decision curve analysis (DCA) evaluated performance and clinical utility.
    RESULTS: Among 985 patients (median age: 57 years), median OS = 8.8 years (95% CI: 6.9-10.5). The three-biomarker model yielded HR = 4.10 (95% CI: 2.41-6.98, p < 0.001) for high- vs. low-risk groups in the validation cohort, comparable to the four-biomarker model (HR = 4.24, p < 0.001). Surgery was associated with improved OS in high-risk (HR = 0.45, p = 0.001) but not low-risk (HR = 0.83, p = 0.72) patients, consistent with the original model. The models performed similarly across all metrics (e.g., Concordance Index: 0.71 vs. 0.72; Brier Score: 0.22 for both) as was model fit (Likelihood Ratio Test: p = 0.066). DCA revealed comparable clinical benefit.
    CONCLUSION: Removing survivin preserves PREDICTR-OPC's predictive performance, offering a more cost-effective, easier-to-implement tool for OPSCC treatment recommendations.
    LEVEL OF EVIDENCE: 3:
    Keywords:  human papillomavirus; oropharyngeal squamous cell carcinoma; prognostic model; surgical escalation
    DOI:  https://doi.org/10.1002/lary.70611
  20. Mol Ther Adv. 2026 Jun 11. 34(2): 201730
    IL-12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer.
    Lupita S Lopez, Ziyou Cui, Yukiko Yamaguchi, John P Murad, Zhiyuan Yang, Ke Zou, Jason Yang, Wen-Chung Chang, Stephen J Forman, Vivien W Chan, Saul J Priceman.
      Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single-chain variable fragment (scFv) derived from the humanized murine mAb clone J591 as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFN-γ production, and anti-tumor cell activity in vitro. Using two clinically relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.
    Keywords:  T cell; adoptive cellular immunotherapy; chimeric antigen receptor; membrane-bound IL-12; prostate cancer; prostate specific membrane antigen
    DOI:  https://doi.org/10.1016/j.omta.2026.201730
  21. Nat Commun. 2026 May 12.
    E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer.
    Lounes Djerroudi, Rana Mhaidly, Yann Kieffer, Isabelle Damei, Hugo Croizer, Vithuzane Selvarasa, Geraldine Gentric, Laetitia Fuhrmann, Andreia Goncalves, Martial Caly, Camille Richardot, Renaud Leclere, Enora Laas, Caroline Malhaire, Kim Cao, Julia M Houthuijzen, Pim Kloosterman, Jos Jonkers, Camille Benoist, Victor Renault, François-Clément Bidard, Anne Vincent-Salomon, Fatima Mechta-Grigoriou.
      Invasive lobular breast carcinoma (ILC) shows specific stromal features, and a high tumor-infiltrating lymphocyte (TIL) content being associated with poor patient prognosis. Here, we reveal the underlying mechanism by performing single-cell analysis, immunohistochemistry, deconvolution of bulk RNA-sequencing in a large female ILC series and functional assays. We show that E-cadherin (CDH1)-loss in breast cancer cells prevents differentiation of FAP+ inflammatory cancer-associated fibroblasts (iCAF) into FAP+ myofibroblastic CAF, leading to iCAF accumulation in ILC. In turn, FAP+ iCAF attract TILs into the tumor center, shaping their spatial organization. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape through a lack of retention and activation of ITGAE-expressing resident memory CD8 + T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, FAP+ iCAF and CD8 + TRM, providing insights into the ILC stromal reaction and revealing why and how TILs are associated with poor prognosis in ILC patients, a mechanism generalizable to other CDH1-inactivated cancer types.
    DOI:  https://doi.org/10.1038/s41467-026-72844-4
  22. Clin Med Insights Oncol. 2026 ;20 11795549261446733
    Advances in Immunotherapy for Head and Neck Squamous Cell Carcinoma: Focus on PD-1/PD-L1 Blockade and Beyond.
    Fei Le, Youfang Jiang, Yaoyao Chen, Xianming Huang, Qian Ouyang, Saiping Lü.
      Head and neck squamous cell carcinoma (HNSCC) ranks as the seventh most common cancer globally, with etiological subtypes-carcinogen-driven (human papillomavirus [HPV-negative]) and HPV-driven-shaping tumor immunogenicity and treatment responses. This review highlights immunotherapy's evolution, focusing on PD-1/PD-L1 blockade. HPV-positive tumors feature a "hot" microenvironment with dense tumor-infiltrating lymphocytes (TILs) and PD-L1 upregulation, yielding better immune checkpoint inhibitor (ICI) outcomes. In contrast, HPV-negative cases exhibit a "cold," immunosuppressive profile with inferior ICI responses. Landmark trials like KEYNOTE-048 and CheckMate 141 established pembrolizumab and nivolumab as standards for recurrent/metastatic HNSCC, improving median OS (overall survival) by 2 to 4 months over the EXTREME regimen (cetuximab plus platinum-based chemotherapy), especially in patients with PD-L1 Combined Positive Score (CPS) ⩾ 1. Combination strategies enhance efficacy through multiple mechanisms: chemotherapy induces immunogenic cell death, radiotherapy elicits abscopal effects, and cetuximab provides additional antitumor activity. In locally advanced disease, the KEYNOTE-689 trial demonstrated superior event-free survival with perioperative pembrolizumab versus placebo (59.7 vs 29.6 months), supporting treatment de-escalation strategies. Management of immune-related adverse events follows established NCCN/SITC guidelines. Emerging therapies, including anti-LAG-3/TIM-3 and oncolytic viruses, target resistance. Future efforts emphasize multiomic biomarkers and equitable access to optimize outcomes in this heterogeneous malignancy.
    Keywords:  PD-1/PD-L1 blockade; adverse events; combination therapy; emerging agents; head and neck squamous cell carcinoma; immunotherapy; neoadjuvant therapy
    DOI:  https://doi.org/10.1177/11795549261446733
  23. Nat Biotechnol. 2026 May 13.
    Immune-remodeling mRNAs expressing IRF8 or NIK generate durable antitumor immunity in multiple cancer models.
    A Gupta, R Das, K Reed, T Jeon, Q T C Nguyen, A Rudra, X Ge, S Trongjit, Y S Vanrobaeys, R Langer, R Weissleder, C Garris, D G Anderson.
      Although immunotherapy has benefited a subset of persons with cancer, its broader efficacy remains limited, primarily because of an immunosuppressive tumor microenvironment characterized by insufficient numbers of functional tumor-specific T cells, antigen-presenting cells (APCs) and tumor-infiltrating lymphocytes. Here we engineer immune cells in the tumor microenvironment using lipid nanoparticles (LNPs) to deliver immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase or interferon regulatory factor 8. These IR-mRNAs activate APCs in tumors, significantly increasing activated type 1 conventional dendritic cells, immunostimulatory cytokines and priming antitumor CD8+ T cells. IR-mRNAs encapsulated in LNPs elicited durable antitumor responses in multiple syngeneic mouse tumor models through both intratumoral and intravenous delivery. Coadministration of IR-mRNA and ovalbumin mRNA elicited a ~10-fold increase in antigen-specific CD8+ T cell responses, sustained long-term memory and effectively prevented tumor growth in vaccinated mice. Additionally, coadministration of IR-mRNA and hemagglutinin mRNA enhanced the humoral response ~5-fold and the cellular response ~15-fold, underscoring their potential as adjuvants for boosting adaptive immunity.
    DOI:  https://doi.org/10.1038/s41587-026-03115-2
  24. Rev Recent Clin Trials. 2026 May 08.
    Lifileucel: Shedding Light on a New Treatment for Advanced Melanoma.
    Ariana Genovese, Andrea Ashchi Lachapelle, Andrew Ashchi, Kelli Corona, Lauren Carpenter, Andres Valdes, Ashish Kumar, Jessica Huston.
      Lifileucel is a tumor-derived autologous T cell therapy approved for unresectable or metastatic melanoma in adults. This article discusses 10 clinical studies on lifileucel for the treatment of advanced melanoma. The phase II study data available evaluated the safety and efficacy of lifileucel in a global, multicenter study involving adult patients with unresectable or metastatic melanoma who had previously received systemic therapies, including a PD-1 blocking antibody and, if applicable, BRAF and MEK inhibitors. Among 73 patients treated with the recommended dose, the objective response rate was 31.5%, with 4.1% achieving a complete response and 27.4% a partial response. Of the responders, 56.5%, 47.8%, and 43.5% maintained their responses without progression or death at 6, 9, and 12 months, respectively. The most common adverse events seen in clinical studies include thrombocytopenia, anemia, and febrile neutropenia. Additional studies are underway to provide further data on the use of lifileucel as a safe and effective intravenous treatment option for unresectable or metastatic melanoma. This article reviews the published data encompassing the preliminary development, pharmacology, efficacy, and safety of lifileucel.
    Keywords:  AMTAGVI®; LN-144; Lifileucel; TIL; and melanoma; metastatic; tumor-infiltrating lymphocyte; unresectable
    DOI:  https://doi.org/10.2174/0115748871444837260417095431
  25. Front Immunol. 2026 ;17 1801164
    The exploration of iparomlimab and tuvonralimab combined with de-escalated chemotherapy as an innovative neoadjuvant treatment strategy for locally advanced cervical cancer: a case report from the NICE-CC trial.
    Jie Lin, Haixin He, Bin Liu, Tongmei He, Xuemei Lei, Xinye Guo, Xingfa Chen, Xiang Zheng, Yang Sun.
      Recent research has explored the potential of using neoadjuvant dual immune checkpoint inhibitors (ICIs) combined with de-escalated chemotherapy in several locally advanced tumors to determine if such a combined regimen can enhance tumor response while minimizing toxicity. However, few related studies are focused on locally advanced cervical cancer (LACC). In this study, we present a case from the NICE-CC trial evaluating the feasibility of neoadjuvant dual immune checkpoint inhibitor (ICI) combined with a de-escalated chemotherapy regimen for LACC. A patient with stage IIB LACC had a high tumor burden and a presumed "immune cold" status, indicated by PD-L1 negativity with a Combined Positive Score (CPS) of 0. The patient achieved a pathological complete response (pCR) after receiving one cycle of neoadjuvant iparomlimab and tuvonralimab (simultaneously targeting PD-1 and CTLA-4) combined with standard chemotherapy, followed by two additional cycles of iparomlimab and tuvonralimab. Mechanically, the tumor microenvironment (TME) in this case was characterized by an abundance of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which might be associated with improved responses to ICI therapy. In conclusion, this case highlights the potential of one cycle of neoadjuvant dual immunotherapy combined with standard chemotherapy, followed by two additional cycles of dual immunotherapy, for the treatment of LACC. This innovative treatment regimen warrants further investigation in the ongoing NICE-CC trial.
    Keywords:  case report; chemo-immunotherapy; complete response; de-escalated chemotherapy; iparomlimab and tuvonralimab; locally advanced cervical cancer; neoadjuvant
    DOI:  https://doi.org/10.3389/fimmu.2026.1801164
  26. Immunol Invest. 2026 May 11. 1-20
    The Role of Tumour-Infiltrating Lymphocytes in the Immune Microenvironment of Lymphoma and Their Immunotherapeutic Potential.
    Dezhi Yu, Kaiyun Guo, Chao Wang, Yao Zhang, Wu Jian, Ming Lei, Yuting Lei, Chunlian Zhao.
       BACKGROUND: Tumour-infiltrating lymphocytes (TILs), including CD8+ T cells, CD4+ T cells, B cells and natural killer cells, play a key role in anti-tumour immune responses and modulate tumour immune escape via crosstalk with immunosuppressive factors in the tumour microenvironment. Despite inherent anti-tumour activity, TIL function is largely constrained by immune escape and cellular exhaustion. TILs also synergise with PD-1/PD-L1 and CTLA-4 to regulate the magnitude and persistence of anti-tumour immunity, and have emerged as valuable biomarkers for evaluating immunotherapeutic efficacy in lymphoma.
    METHODS: This review systematically summarises recent published literature regarding the biological function, immune regulatory mechanisms and clinical research progress of TILs in lymphoma.
    RESULTS: TILs exhibit promising potential in lymphoma immunotherapy, whereas TIL-based strategies remain challenged by complex cell preparation, unstable therapeutic efficacy and drug resistance. Further research is required to clarify TIL heterogeneity, characterise diverse immune escape mechanisms, and optimise clinical culture protocols.
    CONCLUSIONS: This review clarifies the pivotal role of TILs in the lymphoma immune microenvironment and their immunotherapeutic value. Optimising TIL culture conditions combined with gene editing and bioengineering will improve therapeutic efficacy and clinical applicability, offering novel insights for clinical treatment of lymphoma.
    Keywords:  Immune escape; Tumour-infiltrating lymphocytes; immunotherapy; lymphoma; tumour immune microenvironment
    DOI:  https://doi.org/10.1080/08820139.2026.2645948
  27. Cancer Res. 2026 May 12.
    Soluble Uric Acid Drives CD8⁺ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation.
    Anyi Liu, Fan Zuo, Mao Li, Lanlan Yin, Dongjing Zhang, Lang Liu, Chengxin Yu, Changsheng Huang, Yaqi Chen, Qi Wu, Li Sun, Guihua Wang, Junbo Hu.
      T-cell exhaustion in the tumor microenvironment undermines anti-tumor immunity and limits immunotherapy efficacy. Further defining the metabolic triggers of this dysfunctional state could provide therapeutic targets for circumventing immunosuppression. Here we identified soluble uric acid (UA)-an abundant purine metabolite frequently elevated in cancer patients-as a metabolic checkpoint that drives exhaustion of CD8⁺ T cells and immune evasion in colorectal cancer (CRC). In hyperuricemic mouse models, elevated UA accelerated tumor progression in immunocompetent hosts, but not T-cell-deficient ones, by functionally exhausting tumor-infiltrating CD8⁺ T cells. Mechanistically, UA directly bound the kinase scaffold KSR1 and hyperactivated MEK-ERK signaling, leading to chronic MAPK stimulation that upregulated inhibitory receptors, including PD-1, Tim-3, on CD8⁺ T cells and blunted their cytotoxic function. Genetic disruption of this UA-KSR1-MAPK axis via Tim-3 knockout or Ksr1 knockdown restored T-cell effector activity and tumor control. Notably, pharmacological UA depletion with the clinical xanthine oxidase inhibitor febuxostat reinvigorated CD8⁺ T cells, slowing tumor growth and markedly enhancing the efficacy of both chemotherapy and adoptive T cell therapy in vivo. These findings establish soluble UA as a metabolic immune checkpoint that subverts anti-tumor T-cell immunity. Targeting UA metabolism may offer a strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3911
  28. Mater Today Bio. 2026 Jun;38 103132
    Cyclic mechanical stretch suppresses intrinsic apoptosis in high metastatic melanoma.
    Taehoon Lee, WonJun Jang, Geonwoo Kim, Giheon Ha, Minseok Kim, Soojin Park, Geonho Lee, Hyun-Jong Cho, Yu Shrike Zhang, Han-Jun Kim, Junmin Lee.
      Mechanical forces within the tumor microenvironment are increasingly recognized as important regulators of cancer progression, yet their influence on apoptotic regulation in melanoma remains insufficiently defined. Here, we developed a customized stretchable culture platform capable of delivering physiologically relevant cyclic mechanical strain and investigated its effects on intrinsic apoptosis in melanoma cells with different metastatic potentials. Cyclic stretch significantly reduced apoptosis in high metastatic melanoma cells, while low-metastatic counterparts exhibited minimal or differential responses. Mechanistically, mechanical stimulation suppressed intrinsic mitochondrial apoptotic signaling along the BAD-BCL-2 family-BAX axis, leading to reduced caspase-3/7 activation. Pharmacological modulation of mechanosensitive channel activity and intracellular Ca2+ signaling partially restored apoptotic responses under stretch, supporting the involvement of calcium-associated mechanotransduction in this process. Importantly, stretched high metastatic melanoma cells displayed reduced sensitivity to pharmacological apoptosis induction, indicating altered apoptotic responsiveness under mechanical stimulation. In vivo models further demonstrated that prior mechanical conditioning enhanced survival and metastatic behavior in high metastatic melanoma. Together, these findings reveal that cyclic mechanical stress promotes apoptosis resistance in a metastatic potential-dependent manner and highlight the importance of considering tissue mechanics in understanding melanoma progression and therapeutic response.
    Keywords:  Apoptosis suppression; Cancer therapy; Mechanobiology; Mechanosensitive channel; Metastatic melanoma
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103132
  29. Nature. 2026 May 14.
    Author Correction: Postprandial lipid metabolism durably enhances T cell immunity.
    Alok Kumar, Dayana B Rivadeneira, Isha Mehta, Bingxian Xie, Rachel Cumberland, Supriya K Joshi, Jitendra S Kanshana, William G Gunn, Victoria Dean, Angelina Parise, Kristin Morder, Erica S Myers, Steven J Mullett, Richard T Cattley, Stacy L Gelhaus, Abigail E Overacre-Delgoffe, Jishnu Das, William F Hawse, Alison B Kohan, Greg M Delgoffe.
      
    DOI:  https://doi.org/10.1038/s41586-026-10620-6
  30. J Immunol. 2026 May 14. pii: vkag070. [Epub ahead of print]215(5):
    NDRG3 is essential for sustaining antigen-driven T cell responses by protecting against restimulation-induced cell death.
    Brian J Stack, Susan M Kaech.
      During the response to infections and pathogenic challenges, T cells must expand profoundly and be resilient to repetitive restimulation to clear the ongoing assault and protect the host. This process of prolific expansion is tightly regulated to quickly provide a robust pool of pathogen-fighting T cells, yet also limit excessive expansion to prevent inadvertent damage to host tissues. Restimulation-dependent pro-growth and pro-death signals help regulate this delicate balance of T cell expansion to maintain both host and T cell homeostasis. We have discovered that NDRG3 is a critical determinant of whether T cells proliferate or undergo apoptosis during repetitive restimulation under antigen-driven T cell expansion. CD8+ T cells lacking NDRG3 exhibit severely impaired expansion in vivo in response to both viral infections and tumor challenges. We show that NDRG3 is essential for T cell survival during antigen restimulation by protecting T cells from restimulation-induced cell death (RICD), while it has only a marginal impact on T cell survival in contexts with limited antigen restimulation. Mechanistically, NDRG3 safeguards repetitively stimulated T cells from RICD by constraining FAS-mediated pro-death signaling through caspase-8. Furthermore, NDRG3 overexpression enhanced T cell infiltration into tumors, improving their tumor-controlling capacity. Collectively, these findings establish NDRG3 as a novel, indispensable regulator of T cell responses to foreign challenges. Additionally, this work identifies NDRG3 as a previously undescribed regulator of RICD in T cells and reveals NDRG3 as a potential target for autoimmune disorders and chimeric antigen receptor T cell treatment for cancer.
    Keywords:  NDRG3; T cells; restimulation-induced cell death
    DOI:  https://doi.org/10.1093/jimmun/vkag070
  31. Mol Ther. 2026 May 12. pii: S1525-0016(26)00301-1. [Epub ahead of print]
    IL-15 and IL-21 synergy improves anti-tumor efficacy of iPSC-derived cytotoxic T cells in solid tumors.
    Akihiro Ishikawa, Masazumi Waseda, Tomoko Ishii, Yohei Kawai, Shin Kaneko.
      The development of effective cellular immunotherapies for solid tumors requires the presence of robust infiltration, persistence, proliferation, and antigen-specific cytotoxicity. Here, we engineered induced pluripotent stem cell (iPSC)-derived cytotoxic T cells transduced with a chimeric antigen receptor (iCAR-T cells) and identified an optimal cytokine armoring strategy. Co-expression of interleukin-15 (IL-15) and IL-21 synergistically enhanced STAT1 phosphorylation, leading to increased transcriptional activation of the chemokine receptor CXCR3 and thereby improving tumor homing capacity. Furthermore, the engineered iCAR-T cells maintained a CD45RA-CD45RO+CCR7+CD62L+ memory T cell-like phenotype in tumors, contributing to the prolonged survival of the animal model. These findings demonstrate that cytokine synergy can be engineered into iPSC-derived T cells to overcome significant barriers in solid tumor immunotherapy, offering a scalable approach to developing next-generation off-the-shelf CAR-T therapies.
    Keywords:  CXCR3; JAK-STAT pathway; cancer immunotherapy; iPSC-derived CAR-T cell; iPSC-derived CD8 T cell; interleukin-15; interleukin-21; l; memory T cell; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.036
  32. STAR Protoc. 2026 May 15. pii: S2666-1667(26)00224-8. [Epub ahead of print]7(2): 104571
    Protocol for a multi-modal performance-profiling workflow of CAR T cell products.
    Sarah Schulenberg, Michelle Loeser, Michael Schmueck-Henneresse.
      Functional characterization of engineered T cell products is essential for adoptive cell therapy development. Here, we present multi-modal profiling of CAR T cell products combining 33-marker full-spectrum flow cytometry (FSFC) with live-cell serial tumor-killing imaging. We describe steps for cell preparation, antibody staining, acquisition, serial killing assay, and integrated data analysis. This protocol is readily adaptable to other engineered T cell therapies. For complete details on the use and execution of this protocol, please refer to Schulenberg et al.1.
    Keywords:  Cancer; Cell-based Assays; Flow Cytometry; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2026.104571
  33. Methods Mol Biol. 2026 ;2997 163-173
    Advanced Evaluation of T-Cell-Dependent Bispecific Antibodies Using Fluorescence Imaging and In Vivo Models.
    Mikiko Itsukaichi, Masahiro Yasunaga.
      In this chapter, advanced methods for evaluating T-cell-dependent bispecific antibodies (TDBs) using in vivo fluorescence imaging and animal models are presented. TDBs, which target tumor-associated antigens on cancer cells and the TCR/CD3 complex on T cells, have shown success in hematologic malignancies but face challenges in solid tumors due to factors like reduced T-cell quality and low tumor-infiltrating T cells. Comprehensive protocols for cancer and T-cell preparation, flow cytometry, xenograft model generation, and imaging techniques are outlined, aiming to enhance the understanding of TDB dynamics and improve their efficacy in solid tumor treatment.
    Keywords:  CDX models (cell line-derived xenograft); Cancer immunotherapy; Fluorescence imaging; In vivo models; PDX models (patient-derived xenograft); Solid tumors; T-cell-dependent bispecific antibodies (TDBs); Xenograft models
    DOI:  https://doi.org/10.1007/978-1-0716-5037-0_12
  34. J Exp Med. 2026 Jun 01. pii: e20251779. [Epub ahead of print]223(6):
    PRECISE-seq reveals disease-relevant TCR repertoires with phenotypic plasticity.
    Shibo Liu, Guanghao Liang, Yayun Yang, Yanyang Shi, Lihui Dong, Yue Zhao, Boyuan Mei, Jun Wang, Feng Lin, Yilin Li, Wenxin Dong, Chengyang Liu, Yuhui Cao, Dali Han, Peng R Chen, Meng Michelle Xu.
      Linking T cell phenotypes with antigen specificity and functional avidity is critical for understanding in vivo immune responses in infection and cancer. Here, we develop PRECISE-seq, a method that integrates multi-omics T cell analysis with contact-dependent proximity labeling for rapid screening of disease-relevant T cell repertoires, and for linking the relative TCR avidity with T cell phenotypes at single-cell resolution. PRECISE-seq accurately retrieves CMV-specific clonotypes from human peripheral blood and quantitatively measures functional avidity in physiological contexts. We find that high-potency CMV-specific T cells preferentially acquire an exhausted phenotype. In tumors, polyclonal tumor-reactive CD8+ T cells predominantly differentiate into a protumor Ly49+ regulatory state (TLy49), characterized by inhibitory killer cell lectin-like receptor expression and originating from effector memory T cells along a trajectory distinct from exhaustion. Notably, PD-1 blockade reduces TLy49 formation and promotes effector revival, which correlates with responsiveness to immunotherapy. Together, PRECISE-seq enables high-resolution mapping of TCR potency and T cell phenotype, revealing a regulatory axis shaping T cell fate in tumors.
    DOI:  https://doi.org/10.1084/jem.20251779
  35. Medicine (Baltimore). 2026 May 08. 105(19): e48526
    Constructing a prognostic model for patients over 70 years of age with unoperated non-small cell lung cancer: A LASSO regression method.
    Feiyang Li, Fang Li, Haowei Lu.
      The proportion of elderly patients with non-small cell lung cancer (NSCLC) undergoing surgical treatment is low. However, the prognostic factors influencing the outcomes of nonsurgical patients have not been systematically studied. Therefore, we aim to construct a prognostic prediction model for this patient population to provide a more accurate survival prediction. We conducted a retrospective analysis of patients with pathologically diagnosed NSCLC. We constructed nomograms for overall survival (OS) and cancer-specific survival (CSS) at 1, 3, and 5 years using least absolute shrinkage and selection operator regression and Cox regression analysis. The performance of the predictive models was evaluated using consistency indices, calibration curves, receiver operating characteristic curves, and decision curve analysis. Both internal and external validations were performed. A total of 18,939 NSCLC patients were included, divided into training and validation sets in a 7:3 ratio. The chi-square test indicated no statistically significant difference between the 2 datasets regarding baseline information (P > .05). Through least absolute shrinkage and selection operator regression and Cox regression analyses, we identified age, sex, marital status, American Joint Committee on Cancer stage, radiotherapy, chemotherapy, and distant metastasis as influencing factors for OS. We used these factors to construct a nomogram for OS. Similarly, we identified independent prognostic factors affecting CSS, which included sex, American Joint Committee on Cancer stage, radiotherapy, chemotherapy, and distant metastasis, and constructed a nomogram for CSS. After construction, we validated the prognostic models for OS and CSS using receiver operating characteristic curves, consistency indices, calibration curves, and decision curve analysis, which demonstrated the accuracy and reliability of our models. Finally, we confirmed the feasibility of using these models in different populations through external validation sets. This predictive model can provide a more accurate prognostic assessment for non-operated NSCLC patients over 70 years old.
    Keywords:  NSCLC; SEER database; elderly; nomogram; predictive modeling
    DOI:  https://doi.org/10.1097/MD.0000000000048526
  36. Immunol Med. 2026 May 12. 1-18
    Immune microenvironment and strategy of immunotherapy in acral melanoma.
    Tomoyuki Minowa, Kenji Murata, Stephanie S Watowich, Matthew M Gubin, Yoshihiko Hirohashi.
      Acral melanoma (AM) is a distinct subtype of melanoma that arises on sun protected skin of the palms, soles, and nail beds, and is the most common melanoma subtype in non-Caucasian populations. Despite recent advances in cancer immunotherapy, the efficacy of current immune checkpoint inhibitors in AM remains limited, necessitating tailored approaches for AM that are still undefined. Recent genomic and transcriptomic studies have revealed the unique genetic landscape of AM and its immunosuppressive tumor microenvironment. In this review, we discuss the characteristics of the AM immune microenvironment and highlight key differences compared with cutaneous melanoma. These insights may inform the development of more effective strategies to enhance antitumor immunity in AM.
    Keywords:  Acral melanoma; immunotherapy; tumor microenvironment; tumor-infiltrating T lymphocytes
    DOI:  https://doi.org/10.1080/25785826.2026.2670041
  37. Immunother Adv. 2025 ;5(1): ltaf027
    Head-to-head comparison of nuclear imaging approaches to quantify tumor CD8+ T-cell infiltration.
    Gerwin G W Sandker, René Raavé, Inês F Antunes, Milou Boswinkel, Lenneke A M Cornelissen, Gerben M Franssen, Janneke Molkenboer-Kuenen, Peter J Wierstra, Iris M Hagemans, Erik F J de Vries, Johan Bussink, Gosse J Adema, Martijn Verdoes, Erik H J G Aarntzen, Sandra Heskamp.
       Introduction: Many immunotherapies focus on (re)invigorating CD8+ T cell anti-cancer responses. Different nuclear imaging techniques have been developed to measure CD8+ T cell distributions. Comprehensive comparisons of in vivo and ex vivo T cell labeling methods with respect to tumor and normal tissue targeting and correlation with CD8⁺ T cell presence are lacking, but essential for accurate clinical interpretation. We performed a head-to-head comparison of three CD8+ T cell imaging approaches: 89Zr-labeled Fc-silent anti-CD8 antibody ([89Zr]Zr-anti-CD8-IgG2asilent), ex vivo 89Zr-labeled ovalbumin-specific CD8+ T cells ([89Zr]Zr-OT-I), and 18F-labeled IL2 ([18F]AlF-RESCA-IL2).
    Methods: B16F10/OVA tumor-bearing C57BL/6 mice (n = 10/group) underwent PET/CT imaging at 72 ([89Zr]Zr-anti-CD8-IgG2asilent), 24 and 48 h ([89Zr]Zr-OT-I), and 10 min ([18F]AlF-RESCA-IL2) pi. Subsequently, biodistribution analysis was performed, followed by flow cytometry to evaluate intratumoral CD8+ T cell numbers. Intratumoral radiolabel distributions were assessed by autoradiography and immunohistochemistry.
    Results: All approaches showed uptake in CD8-rich tissues, with preferential spleen targeting. Biodistribution analyses showed tumor uptake exceeded blood level for [89Zr]Zr-anti-CD8-IgG2asilent and [89Zr]Zr-OT-I. Furthermore, their tumor uptake correlated to intratumoral CD8+ T cells presence even though intratumoral distribution patterns differed significantly.
    Conclusion: [89Zr]Zr-anti-CD8-IgG2asilent and [89Zr]Zr-OT-I PET/CT imaging can evaluate intratumoral CD8+ T cell infiltration. [89Zr]Zr-anti-CD8-IgG2asilent might be suited for TME immunophenotyping, while ex vivo labeling visualizes tumor migration and invasion dynamics of tumor-specific T cells. [18F]AlF-RESCA-IL2 uptake did not correlate to the intratumoral CD8+ T cell presence. Here, we provide new insights to guide the selection of imaging strategies for assessing relevant immunotherapy-specific aspects of the TME and support the correct interpretation of clinical CD8 imaging.
    Keywords:  CD8-positive T-lymphocytes; PET/CT; anti-CD8 antibody; ex vivo labeled CD8+ T cells; interleukin-2
    DOI:  https://doi.org/10.1093/immadv/ltaf027
  38. Int J Clin Oncol. 2026 May 11.
    Targeting regulatory T cells in gastrointestinal cancers: current status and future perspectives.
    Koichi Jinushi, Takuro Saito, Yuichiro Doki.
      Although immune checkpoint inhibitors (ICIs) have revolutionized the gastrointestinal cancer treatment landscape, offering durable clinical benefits in a subset of patients, their efficacy remains limited to this subset of patients, underscoring the urgent need to elucidate the mechanisms underlying immune resistance and develop novel therapeutic strategies. Increasing evidence indicates that the immunosuppressive tumor immune microenvironment (TIME) is a major obstacle to effective antitumor immunity, with regulatory T cells (Tregs) emerging as the central cellular mediators of this process. Tumor-infiltrating Tregs possess potent immunosuppressive functions and suppress cytotoxic CD8+ T cell-mediated responses through multiple mechanisms, including interleukin-2 consumption, cytotoxic T-lymphocyte-associated protein 4-dependent inhibitory signaling, and secretion of immunosuppressive cytokines. Recent advances in spatial transcriptomics and single-cell technologies have catalogued substantial functional heterogeneity among Tregs and revealed their preferential accumulation at tumor margins, suggesting a potential link to immune-excluded TIME phenotypes. In this review, we summarize the known Treg-mediated immunosuppressive mechanisms in gastrointestinal cancers, highlight their spatial and functional characteristics within the TIME, and discuss the status of current Treg-targeted immunotherapeutic strategies and possible future strategies to overcome ICI resistance.
    Keywords:  Gastrointestinal cancers; Immune checkpoint inhibitors; Regulatory T cells; Treg-targeted immunotherapy; Tumor immune microenvironment
    DOI:  https://doi.org/10.1007/s10147-026-02990-8
  39. Int Rev Immunol. 2026 May 13. 1-16
    Upregulation of ADAM10 reinforces CD8+ T cells toward exhaustion in the TME.
    Ahmed M E Abdalla, Yu Miao, Yasir A Taha, Ning Meng, Chenxi Ouyang.
      Using cytotoxic CD8+ T cell-mediated cellular immunity has shown considerable efficacy in cancer treatment. However, the effectiveness of these cells against solid tumors is limited by the presence of an immunosuppressive tumor microenvironment (TME), which constitutes complex networks of regulatory pathways and resistance mechanisms. Given its critical role in TME deterioration through shedding of immunosuppressive molecules from tumor and immune cell surfaces, the upregulation of A Disintegrin and Metalloproteinase 10 (ADAM10) expression can reinforce CD8+ T cells into a state of exhaustion. This paper highlights the influence of ADAM10 and its proteolytic products on the primary pathways of CD8+ T cell exhaustion, including the expression of immune checkpoint molecules and modification across CD8+ T cell transcriptional, metabolic, and nutritional states. We remain optimistic about the critical role of ADAM10 in cytokine-induced T cell exhaustion, recruitment of immunosuppressive cells into the TME, and CD8+ T cell death/survival. Gaining significant insights into these processes may offer new strategies to advance CD8+ T cell-mediated cancer therapy.
    Keywords:  +T cell exhaustion; +T cell therapy; CD8; solid tumors; tumor microenvironment (TME); upregulation of ADAM10 expression
    DOI:  https://doi.org/10.1080/08830185.2026.2669732
  40. Adv Sci (Weinh). 2026 May 14. e75695
    Tumor-Infiltrating mregDCs Restrain Anti-Tumor Immunity in Early Relapse HCC.
    Zefan Zhang, Lin Ding, Yu Zhong, Haokang Feng, Linglong Huang, Waidong Huang, Chunqing Wang, Arne Östman, Beili Wang, Jian Zhou, Jia Fan, Wei Guo, Liang Wu, Yunfan Sun.
      Emerging evidence highlights the tumor microenvironment's (TME) role in hepatocellular carcinoma (HCC), yet how tumor-infiltrating myeloid cells drive relapse is unclear. Using full-length single-cell RNA sequencing (scRNA-seq) on samples from primary and early-relapse HCC patients, we identified a dendritic cell subset DC3, which in relapsed tumor exhibited features of mature DCs enriched in immunoregulatory molecules (mregDCs). Mechanistically, mregDCs recruit dysfunctional CD161+CD8+ T cells, which secrete TNF-α, thereby activating the non-canonical NF-κB pathway to promote the differentiation of mature DCs into mregDCs via tumor necrosis factor receptor 2 (TNFR2). Our results from in vivo mouse models demonstrated that dual blockade of TNFR2 and PD-L1 reduced tumor burden more effectively than anti-PD-L1 monotherapy in mregDC-rich HCC. We also found strong interactions between mregDCs and FCN1+ monocytes, a myeloid-derived suppressor cell (MDSC)-like population. Our study characterizes an mregDC-mediated immunosuppressive network in relapse HCC, nominating TNFR2 as a therapeutic target for myeloid-focused HCC immunotherapy.
    Keywords:  CD161+CD8+ T cell; MregDC; immune escape; relapsed HCC
    DOI:  https://doi.org/10.1002/advs.75695
  41. iScience. 2026 Jun 19. 29(6): 115788
    Pulsed photobiomodulation reprograms the tumor immune microenvironment to restore local T cell-mediated antitumor immunity.
    Xiunan Wang, Chuanfang Chen, Yuling Hong, Jia Zhang, Shih-Chin Cheng.
      Developing strategies to precisely modulate the tumor immune microenvironment (TME) is crucial for advancing immunotherapy. Here, we reported that 980-nm pulsed photobiomodulation (PBM) inhibits early tumor growth by locally reinvigorating antitumor immunity, without direct cancer cell cytotoxicity. In syngeneic LLC and MC38 models, daily PBM delayed tumor growth and conferred durable protection upon rechallenge without systemic toxicity, while efficacy was dependent on CD8+ T cells. Single-cell RNA sequencing and flow cytometry revealed that PBM directly alleviates CD8+ T cell exhaustion and enhances their cytotoxic function in a regulatory T cell (Treg)-independent manner, with immunomodulatory effects restricted to irradiated tumor sites, whereas contralateral, untreated lesions remained unaffected, confirming a localized mode of immune modulation. PBM failed against pigmented B16 melanoma, likely due to melanin-mediated light absorption. Collectively, 980-nm pulsed PBM is a localized photo-immunomodulatory strategy that reinvigorates CD8+ T cells, holding potential as a safe adjunct to existing immunotherapies.
    Keywords:  cancer; immunology; photomedicine
    DOI:  https://doi.org/10.1016/j.isci.2026.115788
  42. BMC Med. 2026 May 09.
    Combined targeting of VISTA and sorafenib activates T cell-mediated anti-tumor immunity via the NF-κB/TNF axis in hepatocellular carcinoma.
    Jie Wang, Xueni Zeng, Wenwen Liu, Zhiwei Ou, Wanghui Wu, Sihan Tian, Shulin Li, Xiaodan Tan, Xiaoqing Zhai, Lanqian Li, Meifeng Wang, Wenxi Hua, Jun Long, Yian Wang, Lihong Chen, Wenmin Zhang.
       BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, with most patients diagnosed at advanced stages. Sorafenib, a multi-targeted tyrosine kinase inhibitor, remains a first-line therapy but has limited efficacy as monotherapy. Combining sorafenib with immune checkpoint inhibitors has become a leading strategy for unresectable advanced HCC. However, intrinsic and acquired resistance, together with immune-related adverse events, limit clinical benefit to a subset of patients, highlighting the need for new immunotherapeutic targets. V-domain Ig suppressor of T cell activation (VISTA), an emerging immune checkpoint molecule, is overexpressed in multiple cancers and associated with prognosis, suggesting its therapeutic potential in HCC.
    METHODS: VISTA expression and its association with T-cell infiltration were evaluated in human HCC tissues. An in vitro co-culture system and an orthotopic HCC model in C57BL/6 mice were used to assess the antitumor efficacy of anti-VISTA antibody and sorafenib, alone or in combination. Sequential and concurrent regimens were further compared. The efficacy of combination therapy relative to monotherapy was validated in a patient-derived xenograft (PDX) model in NCG mice with adoptive T cell transfer. Transcriptomic sequencing and functional rescue experiments were performed to investigate the underlying mechanisms.
    RESULTS: VISTA was significantly overexpressed in HCC tissues and positively correlated with T cell infiltration. In the C57BL/6 orthotopic model, only the combination regimen significantly inhibited tumor growth compared with control treatment, whereas neither monotherapy reached statistical significance. Combination therapy enhanced T cell infiltration and cytotoxic function compared with monotherapy. Notably, only concurrent administration significantly suppressed tumor growth, whereas both sequential regimens showed nonsignificant inhibitory trends. In the NCG mouse PDX model, monotherapies produced moderate antitumor effects; the combination group showed significantly greater antitumor activity than anti-VISTA monotherapy and a numerical, but nonsignificant, advantage over sorafenib monotherapy. Transcriptomic profiling and functional rescue experiments implicated the NF-κB/TNF signaling pathway in this synergistic effect.
    CONCLUSIONS: Concurrent VISTA blockade plus sorafenib exerts synergistic antitumor effects in HCC, associated with enhanced T cell function and NF‑κB/TNF pathway modulation. Concurrent treatment showed stronger antitumor trends than sequential regimens. These findings support further exploration of VISTA‑targeted combination immunotherapy and provide insights into optimal regimen sequencing.
    Keywords:  Combination therapy; Hepatocellular carcinoma; Immune checkpoint; Sequential therapy; Sorafenib; VISTA (PD-1H)
    DOI:  https://doi.org/10.1186/s12916-026-04920-x
  43. Pharmacol Res. 2026 May 13. pii: S1043-6618(26)00156-8. [Epub ahead of print]229 108241
    Extracellular vesicles as signal hubs and targeted platforms in hepatocellular carcinoma immunotherapy.
    Jiashuo Li, Guangtan Du, Qianqian Liu, Jing Lv, Weiwei Qi, Haowen Liu, Hongzhao Qi, Wensheng Qiu, Shasha Wang.
      Immunotherapy has transformed the management of hepatocellular carcinoma (HCC), yet its efficacy is frequently limited by the immunosuppressive tumor microenvironment (TME). Building on a systematic overview of current immunotherapeutic strategies, including immune checkpoint inhibitors, adoptive cell therapy, bispecific antibodies, therapeutic vaccines, and cytokines, we identify extracellular vesicles (EVs) as pivotal intercellular signaling hubs that underpin resistance across these diverse modalities. This review delineates the dual role of EVs in HCC immunotherapy, characterizing them as both central mediators of immune evasion and engineerable platforms for targeted therapy. We first synthesize how EVs orchestrate immunosuppressive signaling networks by shuttling immune checkpoint proteins, immunosuppressive protein effectors, regulatory non-coding RNAs, and metabolites to recipient immune and stromal cells, thereby establishing redundant and self-reinforcing suppressive circuits. These pathways drive T-cell exhaustion, M2 macrophage polarization, and expansion of immunosuppressive cell populations, collectively fostering a therapy-resistant niche. We then systematically examine two broad therapeutic strategies: directly targeting endogenous pathogenic EVs to intercept immunosuppressive signaling at its source, and engineering EVs as modular platforms capable of delivering nucleic acids, acting as Cytokine 2.0 platforms, serving as cell-free vaccines, or protecting oncolytic viruses. Furthermore, we highlight the emerging role of EV-based liquid biopsies, in which EV cargo reflects real-time TME dynamics and predicts responses to immunotherapy. Ultimately, this review underscores a paradigm shift; understanding and harnessing EV-mediated signaling is essential to overcoming resistance, while integrating EV-based diagnostics with engineered EV therapeutics paves the way for more precise and effective personalized immunotherapy in HCC.
    Keywords:  Extracellular vesicles; Hepatocellular carcinoma; Immunotherapy; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2026.108241
  44. Biophys Rep. 2026 Apr 30. 12(2): 100-115
    Rapid identification of antigen-specific TCRs for cancer immunotherapy.
    Min Jiang, Wenling Wang, Shuguang Tan.
      T cell receptors (TCRs) can recognize peptides presented by major histocompatibility complex (MHC) molecules, referred to as HLA in humans, which enables the targeted eradication of tumor cells expressing specific antigens. In recent years, TCR-engineered T cell (TCR-T) cell therapy has demonstrated substantial advancements in clinical trials targeting solid tumors. Notably, in August 2024, the U.S. FDA approved the first TCR-T drug for the treatment of advanced synovial sarcoma, representing a pivotal milestone in the field. For the development of TCR-T therapy, identifying tumor-associated antigen epitopes and high-functional TCRs are critical. Here, we present a comprehensive protocol outlining the process of identification of immunogenic epitopes and the efficient screening of antigen-specific TCRs from HLA transgenic mice. Additionally, the protocol encompasses methodologies for TCR-T cell preparation and their functional evaluation in vitro. These approaches provide a robust framework for advancing the development of tumor-specific TCRs and fostering the clinical translation of TCR-T therapies.
    Keywords:  Immunopeptide; Immunotherapy; Single-cell sequencing; T cell receptor; T cell receptor-engineered-T cell
    DOI:  https://doi.org/10.52601/bpr.2025.250003
  45. Cells. 2026 Apr 28. pii: 799. [Epub ahead of print]15(9):
    Patient-Derived Organoid Modeling of Glypican-3 CAR-T Responses in Hepatocellular Carcinoma.
    Bohan Zhang, Yun Deng, Mingshan Zhou, Junfei Chen, Jiawen Wu, Xiaofeng Lian, Miaoxin Zhu, Min Zhou, Jie Cao.
      Glypican-3 (GPC3)-targeted chimeric antigen receptor T (CAR-T) cell therapy is a promising approach for hepatocellular carcinoma (HCC), but marked interpatient variability and antigen heterogeneity limit its broader application. Here, we established a patient-derived organoid (PDO)-based platform to functionally evaluate autologous GPC3-targeted CAR-T cell activity in HCC. HCC PDOs preserved key histologic features and heterogeneous GPC3 expression patterns of the original tumors. In co-culture assays, CAR-T cell cytotoxicity was associated with GPC3 expression levels and was accompanied by IFN-γ and IL-2 release, supporting the feasibility of using PDOs for functional assessment of CAR-T cell sensitivity. We further found that matrix conditions strongly influenced organoid architecture, viral transduction, CAR-T cell infiltration, and killing efficiency, with lower Matrigel concentrations providing a more permissive setting for functional assessment. Importantly, in GPC3-low PDOs, pretreatment with the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) reduced DNA methyltransferase 3 alpha (DNMT3A) expression, increased surface GPC3 expression, and significantly enhanced CAR-T-mediated cytotoxicity. Together, these findings provide proof-of-concept evidence supporting the use of HCC PDOs as a patient-derived platform for modeling selected determinants of GPC3-targeted CAR-T cell activity and for exploring combination strategies to improve therapeutic efficacy.
    Keywords:  chimeric antigen receptor T cell; glypican-3; hepatocellular carcinoma; patient-derived organoids
    DOI:  https://doi.org/10.3390/cells15090799
  46. Nat Commun. 2026 May 15.
    Arid3b suppresses CD8 + T cell infiltration and function in microsatellite-stable colorectal cancer via Runx3.
    Shuo Wang, Sen Hou, Ce Luo, Haorui Zhang, Yiteng Jin, Rui Zhang, Yanping Zhao, Xiaoyu Xiong, Rui Guo, Chao Wang, Yudi Bao, Liang Wen, Deng Pan, Yingjiang Ye, Zexian Zeng, Zhidong Gao.
      Microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) is characterized by a cold tumor microenvironment, with limited CD8⁺ T cell infiltration and poor responsiveness to immune checkpoint inhibitors (ICIs). Here, using an in vivo CRISPR/Cas9 screen in a CMT93 cell-derived murine tumor model, we identify Arid3b as a key negative regulator of CD8⁺ T cell infiltration and antitumor activity. Genetic ablation of Arid3b in CD8⁺ T cells significantly enhances their intratumoral accumulation and promotes robust tumor control. Mechanistically, Arid3b deficiency upregulates Runx3, driving a tissue-resident memory-like phenotype and effector function. Notably, the benefits conferred by Arid3b deficiency are abrogated upon Runx3 deletion, indicating a RUNX3-dependent mechanism. Together, targeting ARID3B could offer a promising strategy to reshape the tumor microenvironment and sensitize MSS CRC to immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-73241-7
  47. Crit Rev Oncol Hematol. 2026 May 13. pii: S1040-8428(26)00260-X. [Epub ahead of print] 105373
    In Vivo Generation of CAR-T Cells: Current Obstacles, Strategic Solutions, and Clinical Translation.
    Ziyu Jiang, Shichu Xu, Wenying Li, Jiannan Chen, Zhigang Guo.
      Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of hematologic malignancies, but conventional ex vivo manufacturing remains costly, labor-intensive, and difficult to scale. In vivo CAR-T generation, which reprograms endogenous T cells directly within patients using engineered vectors, offers a simplified and potentially more accessible alternative. This review outlines the major barriers to in vivo CAR-T development-including inefficient systemic delivery, off-target transduction, the trade-off between transfection efficiency and biosafety, and limited persistence of CAR expression. We summarize emerging engineering strategies such as targeted vector systems, combinatorial T-cell recognition, tunable expression control, and approaches to enhance functional durability. Recent early-phase clinical trials demonstrate the feasibility of in vivo CAR-T induction. We also discuss future opportunities and challenges that will shape the translation of this rapidly evolving therapeutic paradigm.
    Keywords:  In vivo CAR-T; T-cell engineering; gene delivery; gene editing
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105373
  48. Clin Cancer Res. 2026 May 11.
    First-In-Human Trial of Encapsulated Cells Constitutively Expressing Localized IL-2 in Patients with High-Grade Serous Ovarian Carcinoma.
    Helen D Clark, Samira Aghlara-Fotovat, Jake Schladenhauffen, Jonathon Debonis, Juan Carlos Amador-Molina, Amanda Nash, Manish Jain, Ryan Newman, Lauren Jansen, Karen Andreas, Kelly Rangel, Travis T Sims, Bryan Fellman, Claudio Dansky Ullmann, Oladapo Yeku, Amy J Bregar, Andrew M Blakely, Cara Mathews, Oleg A Igoshin, Cara Haymaker, Jose Oberholzer, Peter Rios, Daisy Lopez, Hafsa Nasir, Ira Joshi, Rima Chakrabarti, Omid Veiseh, Amir A Jazaeri, Shannon N Westin.
       PURPOSE: Platinum-resistant high-grade serous ovarian carcinomas (HGSOC) are associated with poor therapeutic outcomes. While HGSOC frequently metastasizes to the intraperitoneal (IP) cavity, the success of IP cytokine therapies, such as IL-2, has been hampered by local toxicity and administration difficulties. AVB-001 is a novel IL-2 delivery system consisting of encapsulated, allogeneic cells engineered for constitutive human IL-2 expression.
    PATIENTS AND METHODS: This is a phase I dose-escalation trial of AVB-001 for the treatment of HGSOC (NCT05538624). A single dose of AVB-001 was administered IP laparoscopically, enabling hIL-2 doses from 0.6 to 3.6 μg hIL-2/kg/day. Safety was evaluated using NCI CTCAE v5.0. Efficacy was assessed via RECIST v1.1 and iRECIST criteria.
    RESULTS: The trial enrolled 14 patients across four dose levels. Three patients (21.4%) experienced grade 3 treatment-related adverse events (TRAEs); no grade 4-5 TRAEs were reported. There was one DLT. There was one unconfirmed partial response, but no confirmed responses (ORR 0%). Stable disease was observed in seven patients, with a median duration of 2.57 months (range 2.03-4.23). The clinical benefit rate was 14.3% (n=2). Pharmacokinetics demonstrated dose-dependent increases in serum IL-2, peaking at 1 day post-implantation. Immunological analyses revealed sustained CD8+ and CD4+ T-cell proliferation without corresponding proliferation in regulatory T cells. Dose-dependent CTLA-4 receptor upregulation was observed on CD8+ and CD4+ T cells, whereas PD-1 and TIM-3, remained unchanged.
    CONCLUSIONS: In patients with HGSOC, AVB-001 is safe and effectively activates cytotoxic T cells, supporting further investigation of this locoregional immunotherapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-4142
  49. NPJ Precis Oncol. 2026 May 11. pii: 179. [Epub ahead of print]10(1):
    Multi-omics profiling reveals tumor microenvironment characteristics linked to immunotherapy response and prognosis in non-small cell lung cancer.
    Liangyu Zhang, Jianshen Zeng, Junkai Wen, Zhenyuan Yang, Zhiyi Tian, Menglong Zhang, Xun Zhang, Bin Zheng, Yilin Lin, Fancai Lai.
      Non-small cell lung cancer (NSCLC) patients frequently develop resistance to immunotherapy, underscoring the need for novel predictive biomarkers and a deeper understanding of the underlying mechanisms. In this study, we integrated bulk and single-cell transcriptomic analyses across 31 datasets to elucidate the immune infiltration features distinguishing immunotherapy responders from non-responders. We identified elevated infiltration of ZNF683 + CD8 + T cells as a crucial subset enriched in responders, with ZNF683 expression serving as a robust indicator of immunotherapy responsiveness. By screening 296 algorithm combinations, a ZNF683 + CD8 + T cell-related Riskscore (ZNFRS) was constructed using the optimal StepCox[forward] + Ridge combination, which demonstrated superior prognostic capability for lung adenocarcinoma patients. High-ZNFRS tumors exhibited a "cold" tumor microenvironment (TME) characterized by reduced immune infiltration, immunotherapy resistance, and enhanced SPP1 signaling. In vivo experiments revealed that anti-SPP1 treatment suppressed tumor growth, restored CD8 + T cell effector function, inhibited M2-like macrophage polarization, and significantly enhanced the efficacy of anti-PD-1 therapy. Our findings highlight ZNF683 as a promising biomarker for immunotherapy response and establish the ZNFRS as a robust prognostic indicator. Furthermore, targeting the SPP1 pathway, identified as a key driver of immunosuppression in high-risk patients, represents a viable strategy to enhance anti-PD-1 therapy efficacy in NSCLC.
    DOI:  https://doi.org/10.1038/s41698-026-01474-2
  50. Clin Transl Immunology. 2026 ;15 e70097
    Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss.
    Tianming A Li, Luke T Quigley, Kok Fei Chan, David S Williams, Lisa A Mielke, Andreas Behren, Jessica Da Gama Duarte.
       Objectives: Gamma-delta (γδ) T cells have been associated with favorable prognoses across several malignancies, underscoring their potential as targets for novel immunotherapies. These unconventional T lymphocytes exhibit an intrinsic tropism for the tumor microenvironment, largely driven by their capacity to recognize stress-induced antigens characteristic of metabolically dysregulated tumors. Unlike the mechanism governing conventional cytotoxic CD8+ alpha-beta (αβ) T cells, γδ T-cell receptors can engage tumor cell moieties independent of major histocompatibility complex class-I (MHC-I) and human leukocyte class-I molecules. Therefore, γδ T cells may have a pivotal role in the immune response to beta-2 microglobulin-mutated MHC-I negative (MHC-I-) colorectal cancers (CRCs) with deficient mismatch repair.
    Methods: To determine whether γδ T-cell mobilisation extends to diverse aetiologies of MHC-I loss, we used multispectral immunohistochemistry to stain 150 stage I-IV primary CRC tissues, across eight tissue microarrays.
    Results: Our investigation revealed MHC-I loss in ~30% of CRC primary tumors across all disease stages, with a notable increase in stromal γδ T-cell frequency and activation status among stage III cases. Importantly, these findings extend previous observations largely confined to mismatch repair-deficient CRC by demonstrating that stromal γδ T-cell enrichment associated with MHC-I loss also occurs in mismatch repair-proficient tumors, suggesting a broader role for γδ T cells in immune surveillance of MHC-I-deficient CRC.
    Conclusion: These data highlight the potential of γδ T cells in counteracting immune evasive MHC-I- tumors, thereby offering a robust rationale for their strategic deployment in next-generation immunotherapy regimens.
    Keywords:  MHC class I loss; colorectal cancer; multispectral immunohistochemistry; γδ T cells
    DOI:  https://doi.org/10.1002/cti2.70097
  51. Cancer Cytopathol. 2026 Jun;134(6): e70114
    Prediction of lymphocyte-predominant breast cancer using microRNA expression in cytology specimens.
    Azusa Kai, Koji Arihiro, Hideo Shigematsu, Yukari Ohue-Uchihata, Momoko Nakamura, Ai Amioka, Shinsuke Sasada, Morihito Okada.
       BACKGROUND: Tumor-infiltrating lymphocytes are prognostic and predictive biomarkers of breast cancer; however, conventional assessment is hindered by invasiveness and subjective evaluation, limiting clinical reproducibility. This study investigated the utility of microRNA (miRNA) profiles in predicting lymphocyte-predominant breast cancer (LPBC).
    METHODS: This study included 56 patients with breast cancer who underwent fine-needle aspiration cytology at the time of diagnosis (28 LPBC and 28 non-LPBC cases). Total RNA was extracted from cytology smear specimens, and the expression levels of six candidate miRNAs (miR-30a-3p, miR-187, miR-196b, miR-1247, miR-4485, and miR-6510) were quantified using reverse-transcriptase polymerase chain reaction. The performance in identifying LPBC was evaluated using receiver operating characteristic curve analysis and logistic regression models.
    RESULTS: All six miRNAs showed significantly lower expression levels in the LPBC group than in the non-LPBC group (all p < .05). Receiver operating characteristic curve analysis demonstrated moderate to high diagnostic accuracy, with an area under the curve of 0.708 for miR-30a-3p, 0.739 for miR-187, 0.783 for miR-196b, 0.777 for miR-1247, 0.790 for miR-4485, and 0.673 for miR-6510. Multivariate analysis further identified each miRNA as an independent diagnostic predictor for LPBC.
    CONCLUSIONS: miRNA profiling of cytologic samples enabled the objective identification of LPBC. These findings suggest that specific miRNA expression patterns reflect the tumor immune microenvironment and can be used to evaluate the status of tumor-infiltrating lymphocytes in breast cancer.
    Keywords:  biomarker; breast cancer; cytology; immune microenvironment; lymphocyte‐predominant breast cancer; microRNA; molecular diagnostics; reverse‐transcriptase quantitative polymerase chain reaction (RT‐qPCR); tumor‐infiltrating lymphocytes
    DOI:  https://doi.org/10.1002/cncy.70114
  52. Front Immunol. 2026 ;17 1819997
    Stable global repertoire architecture masks short-term clonal remodeling in intratumoral TCR repertoires.
    Pernille G Pedersen, Odd L Gammelgaard, Sofie Traynor, Christina H Ruhlmann, Aida S Hansen, Henrik J Ditzel, Morten F Gjerstorff, Mikkel G Terp.
       Background: Tumor-infiltrating T cell receptor repertoires are increasingly profiled to assess intratumoral T cell dynamics and inform prognosis and treatment response. Most analyzes rely on aggregate diversity metrics, such as Shannon index or clonality, which describe overall repertoire structure but do not resolve changes in clonotype identity over time. Thus, intrinsic temporal dynamics of intratumoral T cell receptor repertoires during tumor progression remain incompletely defined.
    Methods: In a bilateral murine cancer model, one tumor was surgically removed, and the paired tumor was collected 11 days later. The T cell receptor repertoires of these tumors, and of synchronously harvested bilateral tumors from separate control animals, were analyzed using diversity metrics, Morisita-Horn similarity, and clonal tracking approaches.
    Results: Time-matched bilateral tumors exhibited highly similar clonotype composition and abundance. In contrast, time-separated tumors showed reduced clonal overlap, increased fractions of private clonotypes, and redistribution of dominant clones. These changes occurred despite preserved global repertoire metrics, including clonotype number, Shannon diversity, and Gini coefficient.
    Conclusion: Short-term tumor progression is associated with clear changes in the composition of the intratumoral T cell receptor repertoire, even when overall diversity appears stable. These results suggest that relying solely on global diversity metrics can obscure active clonal remodeling, underscoring the importance of monitoring individual T cell clonotypes to accurately capture intratumoral T cell dynamics over time.
    Keywords:  TCR diversity; TCR repertoire; bilateral tumor; clonal remodeling; temporal TCR remodeling
    DOI:  https://doi.org/10.3389/fimmu.2026.1819997
  53. Sci Rep. 2026 May 12.
    Early FMISO PET changes as exploratory predictors of immune checkpoint inhibitor response in advanced lung cancer: a pilot study.
    Kosuke Hashimoto, Kyoichi Kaira, Hisao Imai, Atsuto Mouri, Ayako Shiono, Yu Miura, Ou Yamaguchi, Tomonori Kawasaki, Hiroshi Kagamu, Ichiei Kuji.
      18F-fluoromisonidazole (FMISO) is a positron emission tomography (PET) tracer used to detect tumor hypoxia. Although FMISO PET has been investigated in several experimental and early clinical studies, its utility for monitoring early treatment responses to immune checkpoint inhibitors (ICIs) remains unclear. Because hypoxia modulates the immunosuppressive tumor microenvironment, this pilot study evaluated whether changes in FMISO uptake before and after ICI initiation could serve as an exploratory predictor of treatment response in patients with advanced non-small cell lung cancer (NSCLC). Seventeen patients with advanced NSCLC who received nivolumab plus ipilimumab (Nivo-Ipi) were enrolled. FMISO PET was performed at baseline and at 9 weeks after treatment initiation. Baseline tumor samples were assessed for CD4, CD8, FOXP3, and PD-L1 expression using standard immunohistochemical procedures. The objective response rate was 52.9%. The median baseline FMISO SUVmax and SUVpeak were 2.7 (range, 1.3-4.8) and 2.5 (range, 1.2-4.5), respectively. Patients who showed a ≥ 20% decrease in FMISO SUV after Nivo-Ipi demonstrated a 77.8% probability of achieving a partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST). FMISO uptake was significantly correlated with 2-deoxy-2-[18F] fluoro-D-glucose accumulation, tumor cell proliferation markers, prealbumin levels, tumor PD-L1, and stromal CD4 expression. When exploratory partial metabolic response (PMR) criteria of a ≥ 20% or ≥ 10% decrease in FMISO SUV were applied, progression-free survival differed significantly between PMR and non-PMR groups, whereas overall survival did not differ significantly. FMISO PET may serve as an exploratory tool for assessing early treatment response to ICIs in patients with advanced NSCLC. However, further studies are required to validate these findings.
    Keywords:  CTLA4; FMISO; Hypoxia; Immunotherapy; Lung cancer; PD-1; PET
    DOI:  https://doi.org/10.1038/s41598-026-50372-x
  54. Tidsskr Nor Laegeforen. 2026 May 12. 146(6):
    Vi må være mer kritiske til temperaturmålinger.
    Sigurd Mydske.
      
    DOI:  https://doi.org/10.4045/tidsskr.26.0138
  55. Research (Wash D C). 2026 ;9 1278
    Tumor-Derived Exosomal Fatty Acids Reprogram Neutrophils to Drive Neutrophil Extracellular Traps Formation and Lung Cancer Progression.
    Lulu Han, Yuxin Chen, Ruchen Wu, Junze Chen, Zhaokai Chen, Ying Cai, Shuxin Huang, Haoqing Gu, Xiaoyi Zhuang, Yanfang Lv, Huizhong Li, Liantao Li, Gang Wang.
      Tumor-infiltrating neutrophils are increasingly recognized as key drivers of cancer progression, but the mechanisms that govern their protumoral reprogramming remain elusive. Here, we demonstrated that lung cancer-derived exosomes (LDEs) deliver free fatty acids into neutrophils, triggering lipid accumulation, fatty acid β-oxidation, and mitochondrial reactive oxygen species production. This metabolic reprogramming culminates in enhanced neutrophil extracellular traps (NETs) formation, which accelerates lung cancer growth. Mechanistically, Ras-related protein Rab-34 (Rab34), a small guanosine triphosphatase, regulates neutrophil uptake of LDEs. Knockdown of Rab34 in neutrophils dramatically attenuated LDEs-induced lipid accumulation, fatty acid β-oxidation activation, and NETs formation, thereby mitigating neutrophil-involved lung cancer progression in vivo. Deoxyribonuclease I-mediated NETs degradation further confirmed the dependency of lung cancer growth on NETs. These findings uncovered a Rab34-dependent way by which LDEs reprogram neutrophils via exosomal free fatty acids, offering Rab34 and NET-associated pathways as potential therapeutic targets in lung cancer.
    DOI:  https://doi.org/10.34133/research.1278
  56. Abdom Radiol (NY). 2026 May 12.
    LI-RADS TRA v2024 succeeds where RECIST and mRECIST fail: viability-based survival prediction in TACE-treated hepatocellular carcinoma.
    Alisa Mohebbi, Mehrad Zare, Afshin Mohammadi, Neda Pak.
       BACKGROUND: Despite robust response assessment validation of Liver Imaging Reporting and Data System Treatment Response Algorithm (LI-RADS TRA) version 2024, a critical evidence gap exists for its prognostic value in non-radiation hepatocellular carcinoma (HCC) therapies. Conventional response assessment criteria (RECIST, mRECIST) focus on morphologic changes, not tumor viability.
    PURPOSE: To evaluate the prognostic implications of LI-RADS TRA v2024 versus RECIST and mRECIST for predicting overall survival and time to progression in HCC patients treated with trans-arterial chemoembolization (TACE), and to assess whether quantitative enhancement reduction augments prognostic stratification.
    METHODS: A total of 105 HCC patients undergoing TACE with multi-phasic contrast-enhanced CT were included. Four board-certified radiologists independently assessed tumor response using LI-RADS TRA v2024, RECIST, and mRECIST criteria.
    RESULTS: LI-RADS TRA demonstrated convergent prognostic discrimination for overall survival, with non-responders achieving mean survival of 719.8 days versus responders 1,002.1 days (p = 0.014; hazard ratio 1.63). In contrast, RECIST (p = 0.670, hazard ratio 0.72) and mRECIST (p = 0.457, hazard ratio 1.16) showed negligible stratification. Importantly, LI-RADS TRA exhibited weak discrimination for time to progression (p = 0.095). Incorporating quantitative enhancement-size change from pre-TACE to post-TACE (%) substantially enhanced LI-RADS TRA prognostic performance for survival (HR 1.91, p = 0.026), but not progression prediction.
    CONCLUSION: LI-RADS TRA v2024 outperforms conventional size-based and enhancement-duration criteria for mortality risk stratification in TACE-treated HCC, reflecting mechanistic potential of viability-based assessment. However, imaging response predicts cumulative mortality, not progression timing. Integration of quantitative enhancement metrics refines risk stratification for surveillance planning.
    Keywords:  LI-RADS TRA; TACE; hepatocellular carcinoma; imaging biomarkers; prognosis
    DOI:  https://doi.org/10.1007/s00261-026-05556-4
  57. Front Immunol. 2026 ;17 1797055
    Eosinophils in lung cancer: from inflammatory cytokines to immunotherapeutic biomarkers.
    Zhen Wang, Fuzhi Jiao, Jing Yuan, Shengnan Zhang, Fenglei Shi.
      Eosinophils, traditionally viewed as effector cells in allergic and parasitic responses, have emerged as multifaceted regulators within the tumor microenvironment (TME). In lung cancer, eosinophils demonstrate complex and context-dependent functions, shaped by chemokines, cytokines, and tumor-derived signals such as CCL11 and IL-33. Recent studies indicate that eosinophils may either promote anti-tumor immunity, by enhancing CD8+ T cell infiltration, secreting cytotoxic granules, and cooperating with IL-33, or facilitate tumor progression through recruitment of regulatory T cells, immune suppression, and expression of immunoregulatory enzymes like IDO. Moreover, eosinophil abundance in tumor tissues and peripheral blood has been associated with both favorable and unfavorable prognostic outcomes in lung cancer patients. Notably, elevated eosinophil counts correlate with improved responses to immune checkpoint inhibitors (ICIs), positioning them as potential biomarkers for immunotherapy efficacy. However, distinctions between tumor-infiltrating and circulating eosinophils, as well as their dualistic roles in metastasis and immune modulation, remain incompletely understood. This review summarizes current advances in understanding eosinophil biology in lung cancer and underscores their promise as diagnostic and therapeutic targets in precision immuno-oncology.
    Keywords:  biomarkers; eosinophils; immune checkpoint inhibitors; immunotherapy; inflammatory cytokine; lung cancer; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1797055
  58. Phys Imaging Radiat Oncol. 2026 May;39 100957
    Estimation of accumulated dose to organs at risk in head and neck cancer patients treated with scheduled replanning and dose painting in the ARTFORCE trial.
    Anna Liza M P de Leeuw, Simon R van Kranen, Jordi Giralt, Yungan Tao, Sergi Benavente, Thanh-Vân F Nguyen, Frank J P Hoebers, Ann Hoeben, Chris H J Terhaard, Lip Wai Lee, Signe Friesland, Roel J H M Steenbakkers, Harry Bartelink, Coen R N Rasch, Jan-Jakob Sonke, Olga Hamming-Vrieze.
       Background and purpose: This study investigated whether scheduled adaptive radiotherapy (ART) improved delivered dose to organs at risk (OAR) in patients with locally advanced head and neck cancer treated with dose painting (DP).
    Materials and methods: Delivered doses were estimated for 81 patients who were prospectively treated with DP + ART using deformable image registration between CBCT and the planning CT's. Three simulations were conducted, evaluating (1) a scenario without replanning (SimnoART), (2) a scenario with ART at fraction 12 (SimART), and (3) the clinical practice with ad hoc replanning (Simdelivered). It was further evaluated whether selecting patients for ART using accumulated dose in the first 10 fractions (Df10) to the parotid glands and larynx would improve ART efficacy.
    Results: In SimnoART, 41% of patients had delivered dose deviations ≥ 3 Gy compared to the planned dose in any OAR, primarily in the parotid glands and larynx. No significant differences were seen between SimnoART, SimART and Simdelivered (P ≥ 0.10). Df10 predicted relevant changes upon completing treatment with AUC ≥ 0.95. By selecting patients for ART using Df10, delivered dose significantly improved for the larynx (P ≤ 0.01).
    Conclusions: Although relevant dose differences between planned and delivered doses were seen in almost half of the patients without ART, minimal improvements in delivered doses were seen introducing ART. Nonetheless, Df10 was prognostic for relevant changes upon completing treatment and selecting patients for ART significantly improved larynx dose. Incorporating accumulated dose into patient selection for ART could help avoid unforeseen increases in delivered dose.
    Keywords:  Adaptive radiotherapy; Dose painting; Head and neck cancer; Replanning
    DOI:  https://doi.org/10.1016/j.phro.2026.100957
  59. Cancers (Basel). 2026 Apr 29. pii: 1423. [Epub ahead of print]18(9):
    A Three-Gene Interferon Signature Predicts Sustained Complete Remission in Pediatric AML Patients.
    Shimaa Sherif, Aesha Ali, Khadega Ibrahim, Darawan Rinchai, Mohammed Elanbari, Dhanya Kizhakayil, Mohammed Toufiq, Fazulur R Vempalli, Tommaso Mina, Patrizia Comoli, Kulsoom Ghias, Zehra Fadoo, Sheanna Herrera, Che-Ann Lachica, Enas D K Dawoud, Hani Bibawi, Sandra Sapia, Blessing Dason, Anila Ejaz, Mohammed Y S Anas, Ayman Saleh, Giusy Gentilcore, Davide Bedognetti, Chiara Cugno, Sara Deola.
      The immunological composition of the microenvironment has shown relevance for diagnosis, prognosis, and therapy in solid tumors but remains underexplored in acute leukemias. We investigated the significance of the acute myeloid leukemia (AML) bone marrow microenvironment in predicting chemosensitivity and long-term remission in pediatric patients. We analyzed 32 non-promyelocytic pediatric AML patients at diagnosis using a NanoString PanCancer IO 360 assay, RNA sequencing, and deep-phenotype flow cytometry analyses. The findings were validated using the pediatric TARGET AML dataset. A short signature of three interferon (IFN)-related genes (GBP1, PARP12, and TRAT1) distinguished patients with chemosensitive disease and reduced minimal residual disease after induction chemotherapy. The signature stratified patients overall, and within the clinically defined "standard-risk" group, patients with high gene expression at diagnosis had significantly longer overall survival. The leukemia microenvironment associated with this signature showed enrichment of non-exhausted CD4+ and CD8+ T cytotoxic lymphocytes and expansion of CD8+ T effector memory cells re-expressing CD45RA (TEMRA) in patients with a favorable prognosis. Our results show the importance of the bone marrow microenvironment in pediatric AML and provide tools for a refined stratification of "standard-risk" patients, lacking adequate risk-oriented therapies. They also offer a promising guide for tackling immune pathways and exploiting immune-targeted therapies.
    Keywords:  AML; bone marrow microenvironment; interferon-related gene signature; tumor
    DOI:  https://doi.org/10.3390/cancers18091423
  60. Oncogenesis. 2026 May 15.
    SHP1 expression in tumor-associated dendritic cells drives immunoevasion via impairing CD8+ memory T cell responses.
    Gao Yu, Yusheng Liang, Weize Yu, Gaojian Zhuang, Bing Li, Jiayi Huang, Jinghao Zheng, Xuanqi Yang, Leyun Wen, Xiaoming Tan, Yuan Zhang.
      Despite the achievements of immunotherapy in the treatment of cancer, overcoming the immune resistance is still an unmet challenge. Dendritic cells (DCs) dysfunction plays a pivotal role in tumor immunoevasion. Previous study uncovered that targeting src homologous region 2 protein tyrosine phosphatase (SHP1) improved anti-PD-1 therapy efficacy in breast cancer by reinvigorating DCs, but the detailed mechanisms remained unclear. Here, we investigated the function of SHP1 in enabling tumor immune escape and suppressing memory T cell formation. Deficiency of SHP1 augmented the activation and antigen-presenting function of dendritic cells, which consequently suppressed the growth of B16-F10 and EMT6 models. We validated this enhanced DC-mediated anti-tumor immunity using conditional knockout mice of SHP1. These results suggested that SHP1 acts as a critical promoter of tumor immune escape. Combining transcriptomic analysis with DC-specific SHP1 deletion, we demonstrated that SHP1 deficiency augments DC immunogenicity via the IFN-γ-JAK1/2-STAT1 pathway. Furthermore, SHP1 blockade promoted the generation of central memory CD8+ T cells, through upregulating the expression of TCF-1, a transcription factor essential for memory lineage commitment. In summary, our research identifies SHP1 as a critical intracellular checkpoint that promotes tumor immune evasion by concurrently suppressing DC antigen presentation and the formation of central memory CD8+ T cells, nominating it as a promising therapeutic target for immunotherapy-resistant cancers.
    DOI:  https://doi.org/10.1038/s41389-026-00627-z
  61. Cancers (Basel). 2026 Apr 29. pii: 1422. [Epub ahead of print]18(9):
    Spatial Proximity Between PD-L1(+) Tumor-Associated Macrophages and CD8(+) T Cells Influences Response to Atezolizumab Plus Bevacizumab in Hepatocellular Carcinoma.
    Takuto Nosaka, Masahiro Ohtani, Junki Yamashita, Yosuke Murata, Yu Akazawa, Tomoko Tanaka, Kazuto Takahashi, Tatsushi Naito, Yoshiaki Imamura, Kenji Koneri, Takanori Goi, Yasunari Nakamoto.
       BACKGROUND: Responses to atezolizumab plus bevacizumab (Atezo+Bev) in hepatocellular carcinoma (HCC) are heterogeneous, and response determinants remain unclear. We investigated whether spatial proximity between PD-L1(+) tumor-associated macrophages (TAMs) and CD8(+) T cells represents an immune niche associated with Atezo+Bev responsiveness.
    METHODS: Multiplex immunohistochemistry was performed on biopsies from patients treated with Atezo+Bev (n = 23) or lenvatinib (n = 20). An interaction variable was defined via nearest-neighbor analysis as CD8(+) T cells within 25 µm of PD-L1(+) TAMs, normalized to cell counts. Associations with tumor shrinkage and progression-free survival (PFS) were examined. CD8(+) T cell phenotypes were evaluated via GZMB and TIM3. Transcriptomic profiling of resected HCCs (n = 8) was conducted using next-generation sequencing and gene set enrichment analysis (GSEA).
    RESULTS: In a patient with responsive and non-responsive lesions, the responsive lesion showed closer PD-L1(+) TAM-CD8(+) T cell proximity. In cohort analyses, the interaction variable was associated with tumor shrinkage and prolonged PFS in the Atezo+Bev group, whereas PD-L1(+) TAM or CD8(+) T cell density alone was not predictive. This association was absent in the lenvatinib cohort. High-interaction tumors showed increased GZMB(+) and TIM3(+) CD8(+) T cells. Transcriptomic analysis revealed the upregulation of inflammatory, cytotoxic, chemotactic, and immunoregulatory genes, with enrichment of the chemokine, IFN-gamma, and IL-10 signaling pathways.
    CONCLUSIONS: Spatial proximity between PD-L1(+) TAMs and CD8(+) T cells defines an immune niche characterized by coexisting immune activation and regulatory programs and is strongly associated with Atezo+Bev responsiveness in HCC. Quantification of this spatial interaction may serve as a biopsy-based biomarker for immunotherapy stratification.
    Keywords:  CD8(+) T cells; atezolizumab plus bevacizumab; hepatocellular carcinoma; spatial immune interactions; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers18091422
  62. Pathol Int. 2026 May;76(5): e70117
    Reinvigorating the Cancer-Immunity Cycle With Combined Oncolytic Virus and CAR-T Cell Therapies in Solid Tumors.
    Keisuke Watanabe, Hiroyoshi Nishikawa.
      Chimeric antigen receptor (CAR)-T-cell therapies have shown remarkable clinical efficacy in hematological malignancies. However, objective clinical responses in solid tumors are limited. Various obstacles, such as the lack of ideal tumor-specific antigens and the immunosuppressive tumor microenvironment (TME), which impairs multiple immunological steps required to achieve effective cancer control, compromise the antitumor efficacy of CAR-T-cell therapy in solid tumors. To address this issue, combination treatment with oncolytic viruses (OVs) and CAR-T cells is being explored. OVs can modulate immunosuppression in the TME and invigorate both endogenous and adoptively transferred T cells, in addition to directly killing tumor cells. The immunomodulatory effect is further augmented by the use of OVs with therapeutic transgenes as payloads. Many preclinical evaluations have provided promising evidence for the combination approach, and clinical studies are ongoing. In this review, the mechanisms underlying resistance to CAR-T-cell therapies and recent advances in combination therapy with OVs and CAR-T cells are discussed from the perspective of the cancer-immunity cycle.
    Keywords:  adoptive cell therapy; cancer immunotherapy; oncolytic viruses
    DOI:  https://doi.org/10.1111/pin.70117
  63. Cancers (Basel). 2026 Apr 28. pii: 1400. [Epub ahead of print]18(9):
    Selecting Representative Tumour Bed Slices May Allow Reduced Embedding Without Loss of Accuracy in Response Evaluation to Neoadjuvant Immunotherapy in Stage IIIB/C Cutaneous Melanoma.
    Anders Bergström, Axel Nelson, Anne Huibers, Emel Cicek, Åse Silverdal, Martin E Johansson, Katarzyna Lundmark, Jonas Selling, Anders Muszta, Iva Johansson.
      Background/Objectives: Histological assessment of the response to neoadjuvant immunotherapy in stage IIIB/C cutaneous melanoma is commonly performed using the INMC recommendations, which advocate embedding the entire tumour bed. However, this approach is highly resource-intensive. The original Swedish National Clinical Cancer Care Guidelines for Melanoma recommend a reduced embedding strategy, but its diagnostic performance in comparison with full embedding has not been systematically evaluated. We aimed to assess whether a reduced sampling approach based on selecting representative tumour bed slices provides comparable response classification to comprehensive embedding according to the INMC protocol. Methods: Ten consecutive patients with stage IIIB/C melanoma treated with neoadjuvant immunotherapy and subsequent lymph node dissection were included. All lymph node material was completely embedded, and the pathological response was evaluated using INMC criteria. Response classification based on the full embedding of the tumour bed was compared with reduced-sampling approaches that simulate the Swedish National Clinical Cancer Care Guidelines for Melanoma. Agreement between sampling methods was analyzed. Results: Targeted reduced sampling of two slices per lymph node demonstrated complete agreement with the full embedding for the INMC response category. Conclusions: In our study, a targeted reduced-embedding strategy focusing on slices with the largest area of tumour bed enables accurate histological assessment of response to neoadjuvant immunotherapy in stage IIIB/C melanoma while substantially reducing workload. These findings support the feasibility of targeted reduced embedding of instructions in the Swedish National Clinical Cancer Care Guidelines for Melanoma as an efficient alternative to full embedding of the lymphadenectomy specimens.
    Keywords:  melanoma; neoadjuvant immunotherapy; pathological response; residual viable tumour; tumour bed
    DOI:  https://doi.org/10.3390/cancers18091400
  64. Comput Struct Biotechnol J. 2026 ;35(1): 0092
    PRDM1 Is Associated with Chemoradiotherapy-Associated Enrichment of Adaptive NK Cells in Cervical Cancer.
    Meng Wan, Tangwu Zhong, Wenyang Shi, Jianyu Shen, Wei Zhang, Yizhe Sun.
      Chemoradiotherapy (CRT) induces tumor cell death and remodeling of the tumor immune microenvironment. Adaptive natural killer (aNK) cells, initially characterized in chronic viral infection, are now recognized as important in solid tumors, contributing to antitumor immunity and immune memory. However, the dynamics of aNK cell response to CRT and the regulatory mechanisms behind their activation are not well understood. We analyzed single-cell RNA sequencing data from cervical cancer patients before CRT, after the first CRT fraction, and after the second fraction. We found that CRT markedly enriched aNK cells, with increased cytotoxicity and enhanced virus-defending programs. Among the differentially expressed genes, the transcription factor PRDM1 (PR/SET domain 1, also known as BLIMP-1:B lymphocyte-induced maturation protein 1) was consistently up-regulated in aNK cells after both rounds of CRT. To explore the potential role of PRDM1, we performed in silico perturbation analyses using scTenifoldKnk and CellOracle. These computational simulations predicted reduced effector-associated programs and perturbed metabolic networks following PRDM1 disruption in aNK cells. Moreover, PRDM1 perturbation altered inferred cellular trajectories, opposing the transcriptional shift toward an adaptive NK-associated state, suggesting that PRDM1 may contribute to maintenance of aNK-associated identity and functional features in the CRT-conditioned tumor microenvironment. These findings identify PRDM1 as a candidate regulator associated with aNK cell enrichment, activation-related remodeling, and trajectory-associated changes following CRT, providing insight into immune remodeling during CRT and highlighting PRDM1 as a promising regulatory candidate for future investigation in radiotherapy-induced antitumor immunity.
    DOI:  https://doi.org/10.34133/csbj.0092
  65. Immunity. 2026 May 12. pii: S1074-7613(26)00168-8. [Epub ahead of print]59(5): 1171-1173
    CD8+ T cells turn resilient under stress.
    Daniele C Nascimento, Luciana Berod.
      Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving effector function and supporting antitumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.006
  66. Appl Immunohistochem Mol Morphol. 2026 May 12.
    Exploring the Immune Microenvironment for Predicting Immunotherapy Efficacy in Epstein-Barr Virus-Associated Gastric Cancer.
    Yunjoo Cho, Sung Hee Lim, Seung Tae Kim, Jeeyun Lee, Kyoung-Mee Kim, Soomin Ahn.
      Epstein-Barr virus-associated gastric cancer (EBVaGC) represents an immunogenic subtype of gastric cancer. However, the effectiveness of anti-PD1 agents in EBVaGC remains uncertain, and reliable predictive biomarkers are currently unavailable. Patients with metastatic EBVaGC (n=12) who received anti-PD1 therapy were included. Histologic subtypes were assessed on hematoxylin and eosin-stained slides; PD-L1 expression was evaluated using conventional immunohistochemistry; the immune microenvironment was further characterized by multiplex immunohistochemistry; and all findings were correlated with response to anti-PD1 therapy. Treatment response varied significantly according to the histologic immune classification of EBVaGCs ( P =0.027). A response to treatment was observed in 71.4% (5/7) of carcinomas with Crohn disease-like reactions, whereas no response was observed in conventional adenocarcinomas (0/5). No significant difference was found in the PD-L1 combined positive score between responders and nonresponders, despite a trend toward higher scores in responders ( P =0.081). Quantitative expression measurements using multiplex immunohistochemistry revealed different tumor microenvironments between responders and nonresponders. Higher numbers of PD-L1 + cells ( P =0.048), CD8 + /PD-L1 + cells ( P =0.029), CD4 + cells ( P =0.048), and CD4 + /FOXP3 + cells ( P =0.005) were observed in responders compared with nonresponders. In the tumor area, a higher number of CK + /PD-L1 + cells was observed in responders ( P =0.038). The immune microenvironment was found to influence the response to immunotherapy in EBVaGC. Detailed characterization of the immune microenvironment may enhance the selection of patients with EBVaGCs likely to respond to immunotherapy.
    Keywords:  Epstein-Barr virus infections; immune checkpoint inhibitors; immunohistochemistry; stomach neoplasms; tumor microenvironment
    DOI:  https://doi.org/10.1097/PAI.0000000000001321
  67. Mater Today Bio. 2026 Jun;38 103128
    Injectable and viscoelastic click alginate hydrogels for spatio-temporal T cell administration in vivo.
    Jone Berasain, Sara Manzano, Oihane Mitxelena-Iribarren, Unai Heras, Ainhoa Romo-Valera, Peio Azcoaga, Leire Iturriaga, Leire Egia-Mendikute, Asís Palazón, Mercedes Fernández, María M Caffarel, Robert Aguirresarobe, Amaia Cipitria.
      T cell therapies have shown limited success in solid tumors, mainly due to the difficulty of T cells to penetrate the tumor tissue. Here, we develop injectable and viscoelastic click alginate hydrogels for local and sustained delivery of T cells, with the goal to improve T cell administration, viability, proliferation, and persistence in vivo. Oxidized alginate (Alg), functionalized with norbornene and tetrazine for inverse electron demand Diels-Alder covalent click crosslinking, at varying low (1% Alg) and high (2% Alg) alginate concentration were used. 1% Alg hydrogels showed better injectability in a fully crosslinked state, characterized by lower stiffness, larger mesh size, viscoelastic behavior, lower injection forces and higher cell viability upon injection. In vitro experiments demonstrated that 1% Alg supported T cell viability and proliferation, and promoted sustained release for 10 days. Using an in vivo chick chorioallantoic membrane (CAM) model, hydrogel-based T cell administration exhibited better local delivery, proliferation and persistence over time compared to bolus injection, with 1% Alg showing enhanced T cell release compared to 2% Alg. Further, in a murine model with a local injection in the mammary gland, 1% Alg showed enhanced T cell persistence within the mammary gland and high tissue integration. In conclusion, we engineered injectable, viscoelastic click alginate hydrogels that support T cell administration, local injection, viability, proliferation and persistence in vivo, opening future opportunities for spatio-temporal control of T cell immunotherapies.
    Keywords:  Chick chorioallantoic membrane (CAM) model; In vivo mouse model; Injectable hydrogel; T cell delivery; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103128
  68. Adv Sci (Weinh). 2026 May 14. e75651
    T-Cell Exhaustion in the Tumor Microenvironment: Subcellular Dysfunction, Pan-Cancer Characteristics, and Therapeutic Interventions.
    Mingxing Wang, Wanhui Dong, Jian Chen, Zhangjie Zhou, Shujuan Fu, Tingting Wu, Haiyan Jiang, Zhiying Wang, Zhixian Zhong, Yi Zhong.
      Although immune checkpoint blockade (ICB) therapy has profoundly reshaped the landscape of oncology, T-cell exhaustion (Tex) remains a core challenge in immunotherapy for solid tumors. Current research predominantly focuses on signal transduction and epigenetic regulation, whereas the adaptive alterations and dysfunction of subcellular organelles within T cells under the stress of the tumor microenvironment (TME) have not been systematically elucidated. This review proposes that suborganellar dysfunction serves as a key functional link in the progression of Tex. We systematically explore the role of dysregulated organelle interaction networks in this exhaustion, including mitochondrial dynamics and metabolic perturbations, aberrant endoplasmic reticulum (ER) stress responses, and mechanical stress-induced nuclear damage, elucidating how these alterations form a self-sustaining vicious cycle. Furthermore, we summarize the heterogeneity and commonalities of T-cell subcellular dysfunction across various solid tumors, such as oxidative stress-mediated mitochondrial damage in lung cancer, aberrant lipid metabolism-induced ER stress in hepatocellular carcinoma, and the suppression of lysosomal function in highly glycolytic tumors. Finally, we review emerging interventional strategies targeting these organelle checkpoints, such as nanomaterial-based mitochondrial protection, delivery systems modulating ER homeostasis, and stimuli-responsive matrix regulation technologies, aiming to provide novel perspectives for enhancing the anti-tumor efficacy of T cells via subcellular engineering approaches.
    Keywords:  T‐cell exhaustion; engineering strategies; immunotherapy; nanomedicine; organelle crosstalk; subcellular remodeling
    DOI:  https://doi.org/10.1002/advs.75651
  69. Mo Med. 2026 Mar-Apr;123(2):123(2): 136-141
    Allogenic Memory-Like Natural Killer Cell Therapy.
    Alaa M Khalifa, Melissa M Berrien-Elliott.
      Adoptive cell therapy has witnessed significant progress with the success of chimeric antigen receptor (CAR) T cells for treating cancer. However, their autologous nature limits scalability, and increases production time and manufacturing costs. Additionally, CAR-T cell administration can result in severe toxicities, including cytokine release syndrome (CRS) and neurotoxicity. To address these issues, allogeneic, natural killer (NK) cells are being explored as an alternative. NK cells are cytotoxic lymphocytes that play a pivotal role in tumor surveillance and eradication. Unlike T cells, NK cells can identify and eliminate targets without MHC restriction or prior sensitization. Furthermore, NK cells exhibit enhanced responses after exposure to virus infections or cytokine activation (cytokine induced memory-like). Allogeneic NK cell therapies offer a promising alternative to autologous cell therapies, with reduced risk of graft-versus-host disease and rapid availability. This review summarizes the current landscape of allogeneic memory-like NK cell therapies, including clinical applications and challenges.
    Keywords:  Transplantation; adoptive transfer; cancer immunotherapy; natural killer cells
  70. Front Immunol. 2026 ;17 1775981
    Translational potential of γδ T cells in hematologic diseases: from immunobiology to therapeutic innovation.
    Xiaokuan Zhou, Mengqi Zhai, Zhe Zhang, Guojun Zhang.
      Hematologic disorders, including malignant and autoimmune conditions, present persistent clinical challenges characterized by relapse, treatment resistance, and profound immune dysregulation. While conventional immunotherapies have advanced, their efficacy is frequently limited by HLA downregulation and effector T cell exhaustion. In this context, γδ T cells offer a promising therapeutic alternative. Recognizing antigens independently of MHC restriction, γδ T cells possess intrinsic tissue-homing capabilities and exhibit dual cytotoxic and immunoregulatory functions. These properties make them highly suitable candidates for allogeneic, "off-the-shelf" cellular therapies where αβ T cells face alloreactive limitations. This review systematically synthesizes the immunobiology of γδ T cells, exploring the functional heterogeneity of specific subsets and their regulation within the tumor microenvironment (TME). We critically evaluate recent preclinical and clinical evidence supporting adoptive transfer, CAR-γδ T strategies, and combination regimens across acute leukemias, lymphomas, multiple myeloma, and immune cytopenias. Furthermore, we address critical translational barriers-including in vivo persistence, subset exhaustion, and manufacturing variability-and discuss rational engineering strategies, metabolic preconditioning, and epigenetic modulation as solutions. Ultimately, advancing γδ T cell therapies requires overcoming these hurdles to transition them effectively from the bench to mainstream clinical practice.
    Keywords:  CAR-γδ T cell therapy; cytokine plasticity; hematologic malignancies; translational barriers; γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1775981
  71. J Clin Pathol. 2026 May 14. pii: jcp-2026-210673. [Epub ahead of print]
    Clinical utility and prognostic value of GATA3 in epithelioid malignant mesothelioma: a practical and cost-effective approach for resource-limited settings.
    Dina Moustafa Thabit, Dalia M Thabet.
       AIMS: Distinguishing epithelioid malignant mesothelioma (EMM) from poorly differentiated lung adenocarcinoma (PD-LUAD) remains challenging, particularly when 21.7% of PD-LUADs lack lineage-specific markers (thyroid transcription factor-1 (TTF-1)/Napsin A), creating a diagnostic blind spot. While GATA-binding protein 3 (GATA3) is established in sarcomatoid mesothelioma, its complementary diagnostic value and prognostic relevance in EMM are not well defined.
    METHODS: This retrospective study analysed 115 tissue specimens (55 EMMs; 60 PD-LUADs). Immunohistochemistry for GATA3, calretinin, Wilms' tumour gene 1 (WT-1), TTF-1, Napsin A and pan-cytokeratin was performed. Results were correlated with clinicopathological parameters and overall survival (OS) using Kaplan-Meier and multivariate Cox regression analyses.
    RESULTS: GATA3 was expressed in 78.2% of EMM but only 6.7% of PD-LUAD cases (p<0.001). Although not specific enough for standalone diagnosis, GATA3 provided meaningful complementary value: in TTF-1/Napsin A-negative PD-LUAD, GATA3 remained negative in 92.3%, helping to exclude EMM when used within a broader panel. Incorporating GATA3 with calretinin and WT-1 improved panel sensitivity to 96.4% while maintaining 100% specificity.High GATA3 expression in EMM correlated significantly with advanced T stage, higher International Mesothelioma Interest Group stage and poor functional status (Karnofsky performance status/Eastern Cooperative Oncology Group). Multivariate analysis identified GATA3 expression (p=0.037), smoking (p=0.041) and clinical T stage (p<0.001) as independent predictors of shorter OS. A qualitative inverse relationship between tumorous GATA3 and GATA3-positive tumour-infiltrating lymphocytes was also noted.
    CONCLUSIONS: GATA3 serves as a useful adjunct within established immunohistochemical panels, particularly in resolving ambiguity in double-negative PD-LUAD. Beyond its supportive diagnostic role, GATA3 demonstrates independent prognostic significance and may reflect underlying immune-microenvironmental features, meriting further exploration in biomarker-guided therapeutic stratification.
    Keywords:  IMMUNOHISTOCHEMISTRY; Lung Neoplasms; PLEURA
    DOI:  https://doi.org/10.1136/jcp-2026-210673
  72. Transl Oncol. 2026 May 15. pii: S1936-5233(26)00146-4. [Epub ahead of print]69 102809
    Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway.
    Lexin Wang, Honglin He, Ke Su, Yunjing Gao, Ying Luo, Huanhuan Tan, Ziyang Liu, Ke Xu, Yi Li, Xiaosong Li.
       BACKGROUND: CD8⁺ T cell exhaustion is a defining feature of the immunosuppressive TME in ccRCC.
    METHODS: We employed a multi-omics driven pipeline to nominate Nicotinamide N-methyltransferase (NNMT) as a high-confidence therapeutic target in ccRCC. This computational prediction was validated through bulk RNA-seq, single-cell RNA sequencing, and spatial transcriptomics to delineate NNMT-associated molecular and cellular programs. While the discovery phase highlighted endothelial-specific NNMT overexpression, we further validated the functional consequences of NNMT modulation using Caki-1 and A498 cell lines to model the downstream signaling cascades. Functional assays assessed impacts on proliferation, apoptosis, cytokine secretion (IL-6, IL-1β, TNF-α), and TGF-β pathway activity. Immune infiltration and T cell exhaustion signatures were evaluated across TCGA cohorts.
    RESULTS: Multi-omics profiling revealed that NNMT is specifically overexpressed in tumor-associated endothelial cells enriched for active TGF-β signaling and inflammatory cues. High NNMT expression strongly correlated with CD8⁺ T cell exhaustion, elevated apoptotic signaling, and immunosuppressive cytokine production. In functional validation, NNMT knockdown suppressed TGF-β activity, reduced pro-inflammatory cytokines, and restored CD8⁺ T cell infiltration and effector function. Mechanistically, NNMT loss shifted the BAX/Bcl-2 ratio toward apoptosis and increased cleaved caspase-3. Spatial transcriptomics confirmed that NNMT⁺ endothelial cells form an immunosuppressive niche in direct contact with exhausted T cells. We also found that I-BET-762, I-BET-151, PFI-1, and BMS-387032 can target and inhibit NNMT to reduce CD8⁺ T cell exhaustion.
    CONCLUSION: We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC.
    Keywords:  CD8⁺ T cell exhaustion; Clear cell renal cell carcinoma; Multi-Omics; NNMT; TGF-β signaling
    DOI:  https://doi.org/10.1016/j.tranon.2026.102809
  73. NPJ Precis Oncol. 2026 May 12.
    Single-nucleus sequencing dissects the malignant change of early lung adenocarcinoma: SMAD3 suppresses antitumor T cell immunity via ICAM1.
    Zhi Zheng, Shuangqing Liao, Chengfei Yang, Yanqi Li, Kai Wang, Ziqi Huang, Sijin Liu, Zhuoxin Dai, Xiaobing Liu, Peng Dai, Xufeng Deng, Jigang Dai, Quanxing Liu.
      The cellular mechanisms governing the change from pulmonary nodules to early-stage lung adenocarcinoma (LUAD) at single-cell resolution are not yet fully elucidated. In the present study, we employed single-nucleus RNA sequencing (snRNA-seq) on 44 pulmonary nodule and paired normal specimens to investigate this process. Within the epithelial compartment, alveolar type 2 (AT2) cells were categorized into high- and low-malignancy subclusters. Our differential expression analysis identified a significant upregulation of the transcription factor SMAD family member 3 (SMAD3) in the high-malignancy group, which was shown to enhance LUAD proliferation and migration. Mechanistically, intercellular adhesion molecule 1 (ICAM1) was established as a downstream target of SMAD3, playing a pivotal role in mediating intercellular crosstalk between malignant AT2 cells and lymphocytes. Specifically, the interaction between ICAM1 and immunosuppressive CD4+ T cells and immune-eliminating CD8+ T cells was found to dampen T cell-mediated antitumor response. In conclusion, these results reveal that the SMAD3-ICAM1 axis drives the malignant change from pulmonary nodules to early-stage LUAD, underscoring the potential of these molecules as biomarkers to inform diagnosis and surgical decision-making.
    DOI:  https://doi.org/10.1038/s41698-026-01460-8
  74. Liver Cancer. 2026 Mar 05.
    Characterization of Patients with Unresectable Hepatocellular Carcinoma in REFLECT Who Achieved Tumor Response or Alpha-Fetoprotein Response When Treated with Lenvatinib.
    Amit Mahipal, Ann-Lii Cheng, Masatoshi Kudo, Adam Burgoyne, Aparna Kalyan, Riccardo Lencioni, Carlos Lopéz Lopéz, Bruno Daniele, Daniel H Palmer, Ari David Baron, Joong-Won Park, Min Ren, Kalgi Mody, Arndt Vogel.
       Background: The phase 3 REFLECT study (NCT01761266) established lenvatinib's noninferiority to sorafenib for unresectable hepatocellular carcinoma (uHCC). This subanalysis examines patients treated with lenvatinib according to the depth of their tumor response and their status as an alpha-fetoprotein (AFP) responder/nonresponder.
    Methods: Of 478 lenvatinib-treated patients, 194 achieved an objective response by mRECIST per independent imaging review. Patients with tumor response were further categorized by their maximal tumor reduction (assessed every 8 weeks). Patients were also assessed according to their AFP response (≥20% reduction from baseline by week 8) status, including AFP responders (n = 227) and nonresponders (n = 73).
    Results: Median duration of response in patients with ≥75% (n = 59)/≥50% to <75% (n = 72)/≥30% to <50% (n = 63) tumor reduction was 9.1 months (95% CI: 7.4-9.3)/7.3 months (95% CI: 5.5-7.4)/3.7 months (95% CI: 3.7-5.6), respectively. Median PFS/OS were 11.0 months (95% CI: 9.3-12.9)/23.4 months (95% CI: 14.3-30.1) for ≥75% tumor reduction, 9.2 months (95% CI: 7.4-11.1)/19.8 months (95% CI: 14.1-23.1) for ≥50% to <75% tumor reduction, and 7.4 months (95% CI: 5.5-9.2)/14.4 months (95% CI: 13.1-19.1) for ≥30% to <50% tumor reduction, respectively. Efficacy was improved among AFP responders versus AFP nonresponders (objective response rate: 48.0% versus 13.7%; median PFS, 7.4 months [95% CI: 5.6-7.8] versus 3.5 months [95% CI: 1.9-3.7]; median OS, 13.4 months [95% CI: 11.5-14.3] versus 8.3 months [95% CI: 6.5-10.7]). Patients with baseline AFP levels <400 ng/mL had longer median OS (19.0 months; 95% CI: 14.6-22.5) versus those with ≥400 ng/mL (10.1 months [95% CI: 8.5-11.7]).
    Conclusions: This analysis highlights the importance of tumor reduction and AFP response as predictors of survival outcomes in lenvatinib-treated patients with uHCC. These data continue to support lenvatinib as an effective first-line treatment option.
    Keywords:  Alpha-fetoprotein; Hepatocellular carcinoma; Lenvatinib; Liver cancer; REFLECT; Tumor
    DOI:  https://doi.org/10.1159/000551313
  75. Nat Rev Immunol. 2026 May 12.
    A role for CD8+ T cells in lupus nephritis.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-026-01310-5
  76. J Transl Med. 2026 May 09.
    Vδ1 T cells exhibit high lactic acid resistance and antitumor activity in solid tumors.
    Yiming Su, Chang Liu, Chenghong Li, Menghua Cai, Yi Xu, Yu Hu, Hui Chen, Jianmin Zhang, Wei He.
       BACKGROUND: Vδ1 T cells are promising for solid tumor immunotherapy but limited by peripheral rarity and inefficient expansion. This study aimed to establish a scalable expansion protocol and evaluate the therapeutic potential of unmodified and CAR-engineered Vδ1 T cells.
    METHOD: Vδ1 T cells were expanded with a patented humanized Vδ1 TCR antibody plus cytokine cocktail (vs. commercial protocols). Transcriptomic profiling, in vitro cytotoxicity assays, in vivo xenograft experiments (vs. Vδ2 T cells), and PARP1-mediated lactate resistance analyses were performed. MSLN/NCL-targeted CAR-Vδ1 T cells were constructed and validated in OVCAR8-baring mice models.
    RESULTS: Average 1 × 10¹⁰ high-purity Vδ1 T cells were obtained from 10 mL peripheral blood, outperforming commercial protocols. Expanded cells retained a stem-like phenotype, exerted superior antitumor activity vs. Vδ2 T cells, and resisted lactate-induced apoptosis via high PARP1 expression. CAR and IL-15 modified Vδ1 T cells showed potent anti-tumor efficacy.
    CONCLUSIONS: This efficient Vδ1 T cell expansion protocol overcomes key clinical translation barriers. Vδ1 and CAR-Vδ1 T cells represent a novel off-the-shelf immunotherapeutic strategy for solid tumors.
    Keywords:  Chimeric antigen receptor (CAR); In vitro expansion; Lactic acid tolerance; Solid tumor immunotherapy; Vδ1 T cells
    DOI:  https://doi.org/10.1186/s12967-026-08234-7
  77. iScience. 2026 Jun 19. 29(6): 115845
    Immune-metabolic profiling of triple-negative breast cancer during neoadjuvant chemotherapy.
    Runze Shi, Yuheng Pang, Chen Chen, Kexin Liu, Wenjing Wang, Yuefeng Shang, Zhigao Li, He Ren, Wenzheng Wang.
      This multi-omics study investigated immune and metabolic determinants of neoadjuvant chemotherapy (NAC) response in triple-negative breast cancer. Analyzing samples from 32 patients, responders exhibited systemic and intratumoral expansion of metabolically active, functionally competent immune cells, including effector memory T cells and activated dendritic cells with enhanced oxidative phosphorylation. Non-responders displayed immune exhaustion and metabolic suppression, with enriched terminally differentiated T cells and senescent NK cells. Transcriptomic and spatial analyses revealed that non-responder tumors were dominated by hypoxia, driving fatty acid oxidation and lymphocyte dysfunction. These findings demonstrate that pre-treatment immune-metabolic fitness in T and B cells is strongly associated with chemosensitivity, offering a promising avenue for predictive biomarker development.
    Keywords:  Oncology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115845
  78. Semin Hematol. 2026 Apr 17. pii: S0037-1963(26)00027-2. [Epub ahead of print]
    Ten years of clinical genetic therapies for sickle cell disease: Current and future directions.
    Alexis Leonard.
      Gene therapy for sickle cell disease (SCD) has advanced rapidly over the past decade, beginning with the first clinical trial 10 years ago and culminating in FDA approval of ex vivo lentiviral and CRISPR-based therapies in 2023. Investment and scientific interest remain high, with both academia and industry actively pursuing next-generation strategies. The field is also shaped by complex economic realities, the discontinuation of otherwise promising programs, and the shifting role of academia as industry pivots toward in vivo platforms. Emerging in vivo gene therapies offer the potential to simplify delivery, reduce conditioning toxicity, and expand global accessibility, but remain preclinical or early-stage, leaving patients and clinicians to navigate difficult trade-offs between current ex vivo options and waiting on experimental in vivo therapies. Manufacturing, mobilization, and long-term durability continue to pose practical and clinical challenges, while real-world outcomes remain largely unmeasured outside clinical trials. This review synthesizes recent developments in ex vivo and in vivo gene therapy for SCD, highlighting the scientific, regulatory, and economic forces shaping the field. Ongoing challenges, future directions, and the critical importance of long-term follow-up and real-world registries are discussed. By providing a contemporary snapshot, the review contextualizes therapeutic progress, clarifies the trajectory of research, and illuminates how patients are affected by the rapid evolution of gene therapy for individuals with SCD.
    Keywords:  ex vivo; gene therapy; in vivo; sickle cell disease
    DOI:  https://doi.org/10.1053/j.seminhematol.2026.03.013
  79. Adv Sci (Weinh). 2026 May 10. e23574
    MEOX1 Coordinates Autocrine-Paracrine Programs via SPHK1/S1P to Promote Lymph Node Metastasis in Ovarian Cancer.
    Jiajia Li, Xiuling Zhi, Qianhan Lin, Yating Sun, Yihua Sun, Zulimire Abudousalamu, Mengyang Xue, Chang Zheng, Xiaotian Li, Liangqing Yao, Mo Chen.
      Lymph node metastasis (LNM) is a pivotal determinant of poor prognosis in ovarian cancer (OC), yet how tumor-intrinsic programs remodel the microenvironment to enable spread remains unclear.Here, we identify the transcription factor mesenchymal homeobox 1 (MEOX1) as an upstream coordinator, whose overexpression associates with LNM, increased lymphatic density, and poor survival based on integrative analyses of public datasets and our 113-patient cohort. In an in vivo LNM model, MEOX1 overexpression enhances tumor burden, lymphatic vessel density, and LNM, whereas tumor-conditioned medium does not directly activate lymphatic endothelial cells (LECs), implicating stromal intermediates. Spatial transcriptomic and immunostaining analyses confirmed cancer-associated fibroblast (CAF)-LEC proximity and vascular endothelial growth factor-C (VEGF-C) localization within CAFs, supporting a CAF-dependent lymphangiogenic route. Mechanistically, MEOX1 binds the sphingosine kinase 1 (SPHK1) promoter to activate sphingosine-1-phosphate (S1P) synthesis, driving a dual autocrine-paracrine program: sphingosine-1-phosphate receptor 3 (S1PR3)-dependent signaling promotes tumor proliferation/migration, while S1P/S1PR1 reprograms fibroblasts into VEGF-C-secreting, alpha-smooth muscle actin (α-SMA)-positive CAFs that stimulate lymphangiogenesis and LNM; SPHK1 inhibition blunts these phenotypes, whereas S1P supplementation restores them. These findings provide novel insights into lymphatic metastasis and demonstrate that metastatic competence depends not only on intrinsic tumor aggressiveness but also on the acquired ability to construct a pro-dissemination niche.
    Keywords:  MEOX1; SPHK1/S1P signaling; cancer‐associated fibroblasts; lymph node metastasis; ovarian cancer
    DOI:  https://doi.org/10.1002/advs.202523574
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