bims-tuinly 2026-02-22 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–02–22
33 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing.
Prognostic Value of Tumor-Infiltrating Lymphocytes in Resected Pancreatic Ductal Adenocarcinoma: A Single-Center Retrospective Australian Study.
Liver Metastasectomy to Obtain Tumor-Infiltrating Lymphocytes: Technical Considerations and Report on Single-Center Experience.
Tumor-reactive TCRs within exhausted TILs reveal cancer type-specific immune landscapes in renal cell carcinoma.
T cell immunotherapy for solid tumors: limitations, progress, and future prospects.
Does tumor-infiltrating lymphocyte therapy improve survival outcomes in patients with advanced melanoma?
Prognostic significance and clinicopathological association of tumor budding and poorly differentiated clusters in cutaneous malignant melanoma.
Potent cytotoxic tumor-infiltrating lymphocytes can be generated from immune-excluded chondrosarcomas using regulatable membrane-bound IL15.
Cell therapy for brain tumors: The first 60 years.
Gut microbiome-driven modulation of the tumor immune microenvironment optimizes dual checkpoint blockade in advanced non-small-cell lung cancer.
Postradiation angiosarcoma of the breast: a 25-year single-institution analysis of clinicopathological characteristics and immunohistochemical biomarker study.
Adoptive cell therapy for ovarian cancer.
Title: AI-based quantification of tumor-infiltrating lymphocytes with integrative transcriptomics in ovarian clear cell carcinoma: JGOG3025-TR1/A1 study.
Come together: The BE-TILs-Efficient multiplex base editing of tumor-infiltrating lymphocytes.
Tumour-infiltrating lymphocyte therapy in melanoma: ready for prime time?
Case Report: Pathologic complete response in triple negative breast cancer treated with anthracycline free regimen.
High efficiency CRISPR knock-in demonstrates that TCF1 is insufficient to reverse T cell exhaustion.
Spleen volume change as a prognostic and immunologic imaging biomarker in extensive-stage small-cell lung cancer receiving chemo-immunotherapy.
Phenotype of circulating tumor-reactive T cells predicts immune checkpoint inhibitor response in non-small cell lung cancer.
Strengthening Antisense Oligonucleotide-Mediated Anti-Tumor Immunity via Metal-Organic Framework Nanoparticles.
Microwave ablation combined with dendritic cells enhances CD8+ T cell activation in rechallenged tumor mouse model.
SPP1 as a central mediator in the tumor microenvironment: Orchestrating cellular crosstalk, immune evasion, and therapy resistance.
Preclinical evidence of anti-CD19 CAR-T cell in vitro and in vivo efficacy against CD19-expressing acute myeloid leukemia.
Baseline tumor features and systemic immune dynamics underlying efficacy in MSS metastatic colorectal cancer treated with regorafenib, ipilimumab, and nivolumab.
Adoptive γδ T cell therapy controls cytomegalovirus infection in preclinical transplantation models.
Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.
Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives.
Collagen-bearing exosomes from breast cancer-associated fibroblasts promote T cell dysfunction.
Relevance of Chemokines in Mobilizing γδ T Cells in the Biliary Tract Cancer Microenvironment: Potential for γδ T-Cell-Based Adoptive Cell Therapy.
CAR-T manufacturing reduces heterogeneity between CIDP and multiple myeloma patient-derived T cells.
Visible tumor-targeting biohybrid vehicles reprogram cancer-associated fibroblasts to potentiate photothermal immunotherapy.
KRASG12V/HLA-A*02:01-targeted chimeric antigen receptor T cells exhibit potent preclinical activity against solid tumors.
Transduction of Batf family members provides distinct functions to mouse CD8+ T cells.

Phys Biol. 2026 Feb 17.

Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing.

Nikolaos Memmos, Kamran Kaveh, Beau R Webber, Branden S Moriarity, David J Odde.

  Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy, where the lymphocytes of a cancer patient's tumor are harvested, expanded in vitro using IL-2 stimulation, and then infused back into the patient[1], [2]. However, even with the use of TIL therapy, cancer cells can survive for various reasons, such as poor lymphocyte infiltration into tumors, chronic activation of the T cell receptor and the immunosuppressive tumor microenvironment [3].Cytokine-inducible SH2-containing (CISH) protein is a negative regulator of T cell activation, and in a recent clinical trial was knocked out in TILs to improve TIL therapy efficacy [4]. In this study, we developed a mechanistic signaling pathway model to theoretically evaluate the efficacy of CISH knockout (CISH KO) in T cell activation and examine potential alternative target genes that can theoretically be targeted using multiplex gene-editing or drugs to further improve T cell activation and function [5]. Our modeling results demonstrate that CISH knockout increases the transcription of activation biomarkers IL-2 and TNF-α, but also inhibitory biomarkers such PD1 and FasL. Using global sensitivity analysis, we also found that GSK3B, which is responsible for the deactivation of the NFAT, is also predicted to further increase T cell activation when knocked out. In addition, we predict that PDCD1, FAS and CTLA4 can be knocked-out in combination with CISH to further enhance T cell activation and prevent exhaustion and apoptosis.

Keywords:  CISH; TIL; checkpoint; gene editing; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1088/1478-3975/ae4705
Cureus. 2026 Feb;18(2): e103580

Prognostic Value of Tumor-Infiltrating Lymphocytes in Resected Pancreatic Ductal Adenocarcinoma: A Single-Center Retrospective Australian Study.

Harine Siribaddana, Prasad Jayaratne, Sarushen Gounden, Daniel Whittaker, Matthew Burge, Kayla Tran, Jai W Hoff, Chin Li Tee, Manju D Chandrasegaram.

  Introduction Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, even after curative-intent resection. Tumor-infiltrating lymphocytes (TILs) assessed by immunohistochemistry have prognostic value, but standardized assessment on routine H&E sections is not established, particularly in Australian cohorts. This pilot study evaluated stromal TIL density in resected PDAC on H&E sections using the International Immuno-Oncology Biomarker Working Group (ITWG) guidelines and explored its association with survival and key clinicopathological metrics. Methods We conducted a retrospective cohort study of 21 consecutive patients who underwent curative-intent resection for histologically confirmed PDAC at an Australian tertiary center between September 2016 and January 2025. Stromal TIL density was quantified on H&E sections and categorized a priori as low (<15%) or high (≥15%) lymphocytic infiltration of the tumor stroma. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier methods and log-rank tests. Univariable Cox regression was performed, followed by an exploratory multivariable Cox model incorporating stromal TIL category, lymph node ratio (LNR), and vascular invasion. Results Median follow-up was 17 months (range, 3-99), with 11 deaths (52%) and 12 recurrences (57%). Using the prespecified threshold of 15% stromal TIL density, 10 patients had low stromal TILs, and 11 had high stromal TILs. Compared with low TILs, high TILs were associated with improved OS (median not reached vs. 16 months; log-rank p = 0.029) and DFS (median not reached vs. nine months; log-rank p = 0.026). In the exploratory multivariable model, high TILs remained associated with improved OS (HR 0.15, p = 0.033) and DFS (HR 0.18, p = 0.024). A higher LNR was associated with poorer OS (HR 3.42 per 10% increase, p = 0.005) and DFS (HR 2.41 per 10% increase, p = 0.010). When analyzed as a continuous variable (per 5% increase), stromal TIL density showed a consistent direction of effect without statistical significance for OS (HR 0.94, p = 0.155) or DFS (HR 0.94, p = 0.115). Conclusions In this single-center Australian pilot cohort, high stromal TIL density assessed on routine H&E sections was associated with improved OS and DFS following PDAC resection. These findings support the feasibility and potential prognostic utility of stromal TIL assessment using ITWG guidelines and warrant validation in larger multicenter studies.

Keywords:  australia; hematoxylin and eosin; pancreatic cancer resection; pancreatic ductal adenocarcinoma; prognostic markers; survival analysis; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.7759/cureus.103580
Ann Surg Oncol. 2026 Feb 20.

Liver Metastasectomy to Obtain Tumor-Infiltrating Lymphocytes: Technical Considerations and Report on Single-Center Experience.

Lisa M Kenney, Aaron J Dinerman, Alexandra M Gustafson, Abraham A Hakim, Stephanie L Goff, Mei Li M Kwong, Udai S Kammula, Jonathan M Hernandez, James C Yang, Steven A Rosenberg, Nicholas D Klemen.

   BACKGROUND: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) is an FDA-approved treatment for metastatic melanoma and continues to be studied in other cancers. As a common site of metastatic disease, the liver is potentially a useful site for TIL procurement, but only if the procedures can be performed with an acceptably low risk of complications.
METHODS: A retrospective analysis was performed on 158 patients who underwent liver resection for TIL procurement between 2000 and 2024. Patients had metastatic melanoma or epithelial cancers. The primary outcomes were 30 days and 90 days morbidity and mortality.
RESULTS: Liver resection for TIL was performed in 81 patients with melanoma and 77 patients with epithelial cancers. The overall 30 days and 90 days mortality were 1% and 10%, respectively, and no deaths were attributed to surgery. Complication rates (Clavien-Dindo ≥ III) were 5% and 7%, respectively. Viable tumor was confirmed in 100% of resected lesions.
CONCLUSIONS: Liver resection for TIL procurement is feasible and safe in carefully selected patients. Candidate patients should be discussed in a multidisciplinary setting with both medical and surgical expertise reaching a consensus on the optimal site selection to minimize risk and maximize therapeutic success.

Keywords:  Adoptive cell therapy; Hepatobiliary surgery; Immunotherapy; Liver metastasectomy; Metastatic cancer; Surgical oncology; Tumor-infiltrating lymphocytes; Tumor-infiltrating lymphocytes procurement

DOI:  https://doi.org/10.1245/s10434-026-19242-8
Front Immunol. 2026 ;17 1729388

Tumor-reactive TCRs within exhausted TILs reveal cancer type-specific immune landscapes in renal cell carcinoma.

Mitsuru Komahashi, Shun Horaguchi, Kayoko Tsuji, Daisuke Hoshino, Takeshi Kishida, Kimitsugu Usui, Noboru Nakaigawa, Shinya Sato, Hiroshi Hamana, Hiroyuki Kishi, Feifei Wei, Yasunobu Mano, Taku Kouro, Shuichiro Uehara, Tetsuro Sasada.

  Clear cell renal cell carcinoma (ccRCC) presents a unique immunological paradox: abundant CD8+ tumor-infiltrating lymphocytes (TILs) correlate with poor prognosis. To clarify their functional status and therapeutic potential, we performed single-cell transcriptomic profiling of TILs from 15 patients with ccRCC and functionally validated dominant T cell receptor (TCR) clonotypes using autologous tumor-derived organoids. Single-cell RNA sequencing revealed dynamic shifts in T cell composition, with effector and progenitor-exhausted CD8+ T cells declining and terminally exhausted CD8+ and regulatory CD4+ T cells enriched in advanced tumors. Despite this exhausted phenotype, in an exploratory analysis with five patients, approximately half of the top 20 TCR clonotypes retained anti-tumor reactivity when re-expressed in non-exhausted T cells, as evidenced by TCR-T cell-mediated cytotoxicity and IFN-γ production against autologous organoids. Transcriptomic signatures enabled the development of a penalized logistic regression classifier that distinguished tumor-reactive from bystander T cells with high accuracy, with AUCs of 0.903 (training) and 0.913 (test). Cross-cancer comparison with pancreatic ductal adenocarcinoma (PDAC) datasets revealed limited generalizability, highlighting the need for cancer type-specific models. Notably, ccRCC-specific TILs exhibited mature, functionally differentiated profiles with limited proliferation, consistent with chronic antigen exposure, whereas PDAC-reactive TILs showed highly proliferative and activated phenotypes indicative of ongoing clonal expansion. Collectively, these findings suggest key features of the immune landscape in ccRCC and provide a preliminary, proof-of-concept transcriptomic framework for prioritizing candidate tumor-reactive TCRs. These insights suggest the feasibility of identifying candidate TCRs for future development of TCR-based adoptive T cell therapies in ccRCC and emphasize the importance of integrating single-cell profiling with functional analyses to refine immunotherapeutic strategies. Given the limited sample size, our results should be considered exploratory and hypothesis-generating, and future studies will be required to validate these findings in larger, independent ccRCC cohorts.

Keywords:  T cell receptor (TCR); TCR-T cell therapy; clear cell renal cell carcinoma; machine-learning; organoid; single-cell RNA sequencing; transcriptome; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1729388
Front Immunol. 2026 ;17 1755751

T cell immunotherapy for solid tumors: limitations, progress, and future prospects.

Yinuo Wang, Boyu Zhang, Yajie Wang, Yuan Tan, Xiaoqian Hu, Xuan Che, Mei Feng.

  T cell-based immunotherapies have achieved notable success in the treatment of hematological malignancies, particularly through the application of chimeric antigen receptor (CAR) T cells. However, the clinical efficacy of such approaches in solid tumors remains limited due to a range of intrinsic and extrinsic barriers, including tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), and insufficient T cell infiltration and persistence. Despite these challenges, significant advances have been made in recent years in the development of CAR-T cells, T cell receptor-engineered T cells (TCR-T), and tumor-infiltrating lymphocytes (TILs) for solid tumors. This review provides a comprehensive overview of the current landscape of T cell immunotherapies targeting solid tumors. We examine the underlying mechanisms and design principles of each therapeutic modality and summarize the clinical progress in a tumor-specific context. Particular attention is given to the biological and technical challenges that impede treatment efficacy, including antigen escape, on-target off-tumor toxicity, and the suppressive features of the TME. Furthermore, we discuss emerging strategies aimed at overcoming these obstacles, such as combinatorial antigen targeting, immune checkpoint blockade, synthetic biology tools, and gene editing technologies. Finally, we outline future perspectives in the field, emphasizing the importance of precision immunotherapy and the integration of multi-omics data to enhance T cell functionality and specificity. This review aims to inform ongoing research and guide the clinical translation of T cell-based therapies for solid tumors.

Keywords:  T cell receptor-engineered T cells; T cell therapy; chimeric antigen receptor T cells; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1755751
Front Med (Lausanne). 2026 ;13 1775031

Does tumor-infiltrating lymphocyte therapy improve survival outcomes in patients with advanced melanoma?

Piper Ridley-Parish.

  Metastatic melanoma is an aggressive form of cancer, with poor patient outcomes when first-line treatments fail. Success has been seen in checkpoint blockade immunotherapies such as anti-PD-1 and anti-CTLA4 treatments, however long-term use results in resistance. Tumor-infiltrating lymphocyte (TIL) therapy is effective in treating melanoma as a second-line option, particularly in cancers such as melanoma, breast and ovarian cancer. With the 2024 FDA approval of Iifileucel (Amtagvi), a type of TIL therapy, this literature review aims to establish how effectively TIL therapy can treat metastatic and advanced melanomas, to evaluate if this type of therapy should be approved in the UK. A detailed search of databases Medline and Cochrane Library was conducted using terms related to "tumor-infiltrating lymphocyte therapy" and "advanced melanoma" focusing on peer-reviewed research and phase II/III clinical trials published between 2015 and 2025. Studies were included if written in English and reported survival-related outcomes. The evidence highlights TIL therapy as an effective treatment for late-stage melanoma, with up to 20% of patients showing complete responses and all studies regarding TIL therapy as equally effective or more successful than the control drugs used. However, some studies reported adverse effects, mostly linked to lymphodepleting chemotherapy. Overall, the literature indicates that TIL therapy is a breakthrough drug that could change the treatment of melanoma, and allow patients another, effective treatment option, after first-line treatments are no longer suitable. This review concludes that future research should focus on larger cohort studies, and cost-effectiveness investigations to support approval in the UK.

Keywords:  CTLA4; IL-2; advanced melanoma; checkpoint inhibitors; metastatic melanoma; tumor-infiltrating lymphocyte therapy

DOI:  https://doi.org/10.3389/fmed.2026.1775031
Virchows Arch. 2026 Feb 20.

Prognostic significance and clinicopathological association of tumor budding and poorly differentiated clusters in cutaneous malignant melanoma.

Yun-Li Xie, Shi He, Shafi Rehman, Shu-Yi Lu, Long-Feng Ke, Wen-Wen Zhang, Yu Chen, Gang Chen, Yan-Ping Chen.

  This study examined the prognostic significance of tumor budding (TB) and poorly differentiated clusters (PDCs) in 232 patients with primary cutaneous melanoma (CM). Through retrospective analysis and Cox regression models, TB-3 and ulceration were identified as independent prognostic factors for overall survival, while AJCC stage IV and PDCs were associated with progression-free survival. Additionally, factors such as ulceration, vascular invasion, lymph node metastasis, TB-3, PDCs, non-brisk tumor-infiltrating lymphocytes (TILs), and Breslow thickness were significantly linked to prognosis. A nomogram developed from these findings demonstrated strong predictive accuracy (AUC = 0.839). The results suggest that incorporating TB and PDCs into the current CM staging systems could enhance risk stratification and clinical decision-making.

Keywords:  Cutaneous melanoma; Poorly differentiated clusters; Prognostic markers; Tumor budding

DOI:  https://doi.org/10.1007/s00428-026-04452-y
Cancer Immunol Res. 2026 Feb 20.

Potent cytotoxic tumor-infiltrating lymphocytes can be generated from immune-excluded chondrosarcomas using regulatable membrane-bound IL15.

Zheng Ao, Rusul Al-Marayaty, Bülent Arman Aksoy, Farres Obeidin, Rachel Burga, Samer Attar, Terrance Peabody, Pedro Hermida de Viveiros, Juliana Chi Kei Ng, Weiqing Jing, Himaly Shinglot, Ali Zhang, Alonso Villasmil Ocando, Nishita Roy, Gauri Kulkarni, Andres Alvarado, Dexue Sun, Dhruv K Sethi, Michelle Ols, Jan Ter Meulen, Seth M Pollack.

Autologous tumor-infiltrating lymphocyte (TIL) cell therapy is showing promising efficacy against immunologically "hot" tumors such as melanoma, cervical cancer, and renal cancer. However, generation of tumoricidal TIL from cold tumors with a low tumor mutational burden, such as many sarcoma types, poses a challenge due to limited infiltration of the tumor microenvironment (TME) with lymphocytes, low frequencies of tumor antigen-specific, high-affinity T cells, and incompletely understood mechanisms of immune-resistance prevailing in the TME. Here, we report the successful generation and expansion of TIL engineered with regulatable, membrane-bound IL15 (cytoTIL15™ cells) from immune-excluded, paucicellular chondrosarcoma biopsies largely consisting of collagenous matrix and demonstrate that these cells have potent tumor-killing capacity in cell culture and in tumor spheroid models in the absence of exogenous IL2. Comprehensive spatial profiling of the TME revealed ubiquitous collagen and myeloid infiltration as major resistance mechanisms, whereas lymphocytic infiltration was largely restricted to peripheral regions of the tumors, a relevant consideration when sampling these tumors for TIL harvest. Moreover, we demonstrate that IL15 reduced the signaling threshold of T-cell receptors isolated from TIL clonotypes, increasing their infiltration and cytotoxicity in autologous 3D tumor models. These results suggest the possibility of developing an effective IL2-free TIL therapy for patients with immune-excluded tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1016
Cell Rep Med. 2026 Feb 17. pii: S2666-3791(26)00043-1. [Epub ahead of print]7(2): 102626

Cell therapy for brain tumors: The first 60 years.

Sanya Mehta, Giedre Krenciute, Stephen Gottschalk.

Primary brain tumors remain among the most lethal cancers, but immunotherapy holds immense potential to overcome limitations of current standard treatment modalities. Since the late 1960s, early-phase clinical trials have iteratively tested cellular immunotherapies for the treatment of brain tumors. Six decades ago, in the earliest studies, brain tumor patients were treated with infusions of nonspecific leukocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells. These earliest studies demonstrated safety and occasional durable antitumor responses, particularly when cell therapies were combined with conventional modalities or administered in the upfront setting. These early cell therapy approaches were chronologically followed by lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), ex vivo nonspecifically expanded and antigen-specific T cells, natural killer (NK) cells, and chimeric antigen receptor (CAR) T cells. In this historical review, we summarize the clinical experience with adoptive cell therapies for brain tumors and review key findings from published clinical studies.

DOI: https://doi.org/10.1016/j.xcrm.2026.102626
ESMO Open. 2026 Feb 16. pii: S2059-7029(26)00019-0. [Epub ahead of print]11(3): 106077

Gut microbiome-driven modulation of the tumor immune microenvironment optimizes dual checkpoint blockade in advanced non-small-cell lung cancer.

Y Katayama, A Fukuda, R Inoue, H Kawachi, R Sawada, T Harada, A Yoshimura, A Okada, S Shiotsu, Y Chihara, Y Takemura, T Yamada, N Nishioka, M Iwasaku, S Tokuda, T Takagi, S Kumagai, S Koyama, K Takayama, T Yamada.

   BACKGROUND: Dual checkpoint blockade with ipilimumab plus nivolumab (I-N), with or without chemotherapy, has shown clinical efficacy for treating advanced non-small-cell lung cancer (NSCLC); however, its benefits are limited to a subset of patients. The gut microbiome influences immune responses and may impact the efficacy of immune checkpoint inhibitors, thus warranting further investigation.
MATERIALS AND METHODS: This prospective study enrolled 50 patients with NSCLC who were treated with I-N, with and without chemotherapy. Gut microbiota diversity and composition were assessed from fecal samples collected before treatment initiation, and tumor-infiltrating lymphocytes (TILs) were evaluated using multiplex immunofluorescence staining. Progression-free survival (PFS), overall survival (OS), and objective response rate were analyzed alongside gut microbiota characteristics and treatment regimens.
RESULTS: High gut microbiota diversity was associated with improved outcomes in patients receiving I-N alone and with greater CD8+ TIL infiltration, particularly PD-1+CD8+ TILs. Responders receiving I-N alone showed enrichment of short-chain fatty acid (SCFA)-producing bacteria, which were linked to favorable metabolic pathways associated with antitumor immune responses. In contrast, the association between gut microbiota diversity and treatment efficacy was not observed in patients treated with I-N plus chemotherapy. Antibiotic use before treatment was independently associated with shorter PFS and OS across all treatment regimens.
CONCLUSIONS: Gut microbiota diversity and SCFA-producing bacteria are associated with improved efficacy of I-N. Baseline gut microbiota diversity may help identify patients who are more likely to have improved outcomes with I-N plus chemotherapy than with I-N alone. These findings highlight the potential of gut microbiota as a novel biomarker for dual checkpoint blockade in NSCLC may contribute to advancing personalized medicine.

Keywords:  antibiotics; dual checkpoint blockade; gut microbiome; non-small-cell lung cancer

DOI:  https://doi.org/10.1016/j.esmoop.2026.106077
Biotech Histochem. 2026 Feb 16. 1-11

Postradiation angiosarcoma of the breast: a 25-year single-institution analysis of clinicopathological characteristics and immunohistochemical biomarker study.

Kristin J Rybski, Brian S Finkelman, Bin Zhang, Ajay Dhakal, Bradley M Turner, David G Hicks, Huina Zhang.

  We examined the clinicopathologic features and immunohistochemical expression of commonly tested biomarkers relevant to targeted therapy in postradiation angiosarcoma (PRAS) of the breast, aiming to better understand tumor biology and provide baseline data on tumor biomarkers to inform future therapeutic strategies for PRAS. Clinicopathologic features, outcomes, and the immunohistochemical expression of tumor biomarkers, including human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and DNA mismatch repair proteins (MMR), were analyzed in breast PRAS specimens diagnosed from 2000 to 2024. A total of 24 breast PRAS specimens from 18 patients were included in the study. All PRAS patients were female, with a median age of 72 years at the time of diagnosis. High-grade tumors were observed in 47%, 43%, and 65% of specimens according to Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC), Donnell-Rosen, and Kuba scoring methods, respectively. Surgical intervention, adjuvant chemotherapy, and radiotherapy were administered to 100%, 29%, and 23% of patients, respectively. Five patients (29%) died from the disease during a median follow-up period of 37 months. Exploratory analysis showed there was no significant association between histologic grade and overall survival, regardless of the grading system used. All PRASs were MMR-proficient with a low number of tumor-infiltrating lymphocytes (TILs) and exhibited an absence of HER2 protein expression. PD-L1 was positive in seven (32%) specimens and positively correlated with stromal TILs. Our findings suggest that breast PRAS are genomically stable and poorly immunogenic, and are likely ineligible for any HER2-targeted therapies based on current approval criteria. A subset of specimens demonstrated PD-L1 positivity, underscoring the need for further investigation of immunotherapy with anti-PD1/PD-L1 immune checkpoint inhibitors as a potential treatment option.

Keywords:  Angiosarcoma; HER2; PD-L1; breast; mismatch repair protein; postradiation angiosarcoma; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1080/10520295.2026.2626268
Clin Adv Hematol Oncol. 2026 Jan-Feb;24(1):24(1): 40-42

Adoptive cell therapy for ovarian cancer.

Kunle Odunsi.
Cancer Immunol Immunother. 2026 Feb 16. 75(3): 81

Title: AI-based quantification of tumor-infiltrating lymphocytes with integrative transcriptomics in ovarian clear cell carcinoma: JGOG3025-TR1/A1 study.

Kohei Hamada, Junzo Hamanishi, Akihiko Ueda, Shiro Takamatsu, Kosuke Yoshihara, Takayuki Nagasawa, Toshiyuki Seki, Akira Kikuchi, Etsuko Fujimoto, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Kazuki Kumada, Katsutoshi Oda, Muneaki Shimada, Aikou Okamoto, Masaki Mandai, Noriomi Matsumura.

  Transcriptomic classification methods have been proposed for ovarian clear cell carcinoma. However, their clinical significance and association with pathologically evaluated tumor-infiltrating lymphocytes (TILs) remain unclear. We established two large transcriptomic datasets and analyzed RNA-sequencing data from 189 (JGOG3025-TR1 cohort) and 38 (Kyoto cohort) ovarian clear cell carcinomas. Representative histopathological slides were also digitized (102 and 38, respectively). Cell types were classified by two state-of-the-art artificial-intelligence models, and TILs were quantified. The transcriptomically defined immune subtype was associated with significantly poor prognosis (hazard ratio, 2.54; 95% CI, 1.42-4.54; p = 0.002 for OS). However, this group also contained significantly higher proportion of advanced-stage cases (p = 0.003), and multivariate analyses showed no independent prognostic effect (hazard ratio, 1.32; 95% CI, 0.68-2.58; p = 0.42 for OS). In contrast, the pathologically defined inflamed group demonstrated a trend toward improved survival, and the inflamed phenotype emerged as a statistically significant favorable prognostic factor for both OS and PFS in multivariate analyses (hazard ratio, 0.32; 95% CI, 0.13-0.78; p = 0.013 for OS. hazard ratio, 0.32; 95% CI, 0.15-0.67; p = 0.0026 for PFS). These findings indicate a discordance between transcriptome- and pathology-based immune classifications and suggest greater prognostic relevance of pathology-derived immune status.

Keywords:  Artificial intelligence; Deep learning; Digital pathology; Ovarian cancer; Prognosis; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s00262-026-04324-z
Mol Ther Oncol. 2026 Mar 19. 34(1): 201135

Come together: The BE-TILs-Efficient multiplex base editing of tumor-infiltrating lymphocytes.

Viktor Glaser, Dimitrios L Wagner, Tobias Bexte.

DOI: https://doi.org/10.1016/j.omton.2026.201135
Br J Cancer. 2026 Feb 18.

Tumour-infiltrating lymphocyte therapy in melanoma: ready for prime time?

Rachel Woodford, Paul Lorigan, Deemesh Oudit, Ahmed Abdulgawad, Fiona Thistlethwaite, Kok Haw Jonathan Lim.

Tumour infiltrating lymphocyte (TIL) therapy offers the potential for durable clinical benefit in select patients with advanced melanoma, especially after progression on treatment with immune checkpoint inhibitors and/or targeted therapies. The 2024 FDA approval of Lifileucel (Amtagvi), a commercially manufactured autologous TIL product, marks a key milestone in integrating advanced therapy medicinal products (ATMPs) into routine care for solid tumours. Health Canada has since approved Lifileucel, with regulatory and funding decisions across the UK and Europe still pending. In this Perspective, we review the evidence base and outline key considerations for national adoption of TIL therapy. Despite promising results from clinical trials, TIL therapy requires complex coordination, including patient selection, tumour procurement, manufacturing logistics, lymphodepletion, and IL-2 administration; all contingent on specialised infrastructure and well-considered integrated care pathways. While commercial centralisation may ease logistical barriers, the high cost of TIL therapy necessitates careful health economic evaluation. A nationally coordinated effort is required to harmonise clinical prioritisation strategies, maintain oversight by multidisciplinary specialist tumour boards, and consider investment in future-proof decentralised manufacturing capacity. Collaborations and peer support such as through the Advanced Therapy Treatment Centre (ATTC) Network will facilitate phased, experience-led rollout with equity-focused service design.

DOI: https://doi.org/10.1038/s41416-026-03350-z
Front Oncol. 2026 ;16 1733621

Case Report: Pathologic complete response in triple negative breast cancer treated with anthracycline free regimen.

Francesca Piazza, Giulia Scartabellati, Laura Moretti, Marta Laganà, Lucia Vassalli, Benedetta Trevisan, Michela Bazzoli, Greta Schivardi, Federico Canzi, Roberto Baraziol, Giuseppe Ippolito, Salvatore Grisanti, Alfredo Berruti, Deborah Cosentini, Rebecca Pedersini.

  Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited therapeutic options and elevated mortality rates. Chemo-immunotherapy according to the KEYNOTE-522 has established a new standard of care in the neoadjuvant setting, due to high rates of pathological complete response (pCR) and improved survival outcomes. Recent evidence suggests the feasibility of treatment de-escalation, particularly the omission of anthracyclines, to mitigate treatment-related toxicity; however, this approach is yet to be established in clinical practice. We report the clinical case of a complete pathological response despite the omission of anthracyclines in a patient with high-risk TNBC. A 54-year-old Caucasian woman was diagnosed in February 2024 with cT4a cN0 TNBC and started neoadjuvant treatment according to the KEYNOTE-522 regimen. Radiologic mid-treatment evaluation showed a marked reduction in tumor size (22 mm vs 78 mm), supporting continuation to the second treatment phase. However, epirubicin extravasation required interruption of treatment, and prompt management of the risk of infection and necrosis was necessary. Once the risk of sepsis was ruled out, the patient underwent surgery, achieving pCR (ypT0, ypN0). This case supports the potential role of de-escalated regimen in selected patients and raises the hypothesis-generating question of whether the inflammatory response triggered by the extravasation of epirubicin has enhanced the immune-mediated anti-tumor effect, potentially making pembrolizumab more effective. The lack of validate predictive biomarkers for patient selection and the absence of reliable imaging techniques to predict pathologic complete response are also discussed. Tumor-infiltrating lymphocytes (TILs) are currently the only biomarkers consistently shown to predict response to neoadjuvant treatment; however, the low TIL level observed in our patient (5%) highlights that this parameter is still far from being a reliable tool to guide treatment de-escalation in clinical practice. Further investigation is warranted to identify which patients could safely benefit from reduced-intensity approaches without compromising outcomes and how clinicians can be guided in this decision-making process.

Keywords:  TNBC; de-escalation; keynote 522; neoadjuvant treatment; pCR; pathologic complete response; side effects

DOI:  https://doi.org/10.3389/fonc.2026.1733621
Nat Commun. 2026 Feb 17.

High efficiency CRISPR knock-in demonstrates that TCF1 is insufficient to reverse T cell exhaustion.

Maria N de Menezes, Amanda X Y Chen, Nihali Kulkarni, Shienny Sampurno, Nicole Y L Saw, Kah Min Yap, Iván Pérez-Núñez, Sara Roth, Christian Deo T Deguit, Brandon Haugen, Kelly M Ramsbottom, Isabelle Munoz, Paul A Beavis, Ian A Parish.

CD8+ T cell exhaustion is a regulatory state triggered by chronic antigen stimulation in both cancer and persistent infection. The less differentiated stem-like sub-populations of exhausted T cells have been heavily studied given their importance to the efficacy of current immunotherapies. While the transcription factor TCF1 is both necessary and sufficient for formation and maintenance of these stem-like populations, it remains unclear whether TCF1 can actively de-differentiate more terminally exhausted subsets back into a stem-like state. To address this question, here we utilize and optimize a high efficiency CRISPR knock-in methodology, compatible with mouse in vivo exhaustion models, to engineer T cells that either constitutively over-express TCF1, or conditionally over-express TCF1 following differentiation of the cells into a CX3CR1+ intermediate-exhausted state. Strikingly, we find that only constitutive, and not conditional, TCF1 over-expression can increase the size of the stem-like T cell pool. Thus, while TCF1 can slow stem-like T cell differentiation, it is insufficient to revert more differentiated cells back into a stem-like state.

DOI: https://doi.org/10.1038/s41467-026-69671-y
Ther Adv Med Oncol. 2026 ;18 17588359261417776

Spleen volume change as a prognostic and immunologic imaging biomarker in extensive-stage small-cell lung cancer receiving chemo-immunotherapy.

Xiuli Liu, Ao Liu, Defeng Liu, Yi Li, Yuanlin Li, Jiazhong Ren, Zhichao Li, Shuqing Duan, Jinming Yu, Minghuan Li.

   Background: The spleen, the largest secondary lymphoid organ, plays an essential role in systemic immune regulation. Its function in tumor progression and treatment response has gained increasing attention.
Objectives: This study aimed to evaluate the prognostic value of spleen volume (SV) change in patients with extensive-stage small-cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy (CIT) and to explore its associations with tumor-infiltrating lymphocytes (TILs) and peripheral immune parameters.
Design: A single-center retrospective cohort study.
Methods: A total of 292 ES-SCLC patients who received first-line CIT were retrospectively analyzed. SV was measured on baseline and post-treatment CT scans, and the relative change was used to classify patients into increased or decreased SV groups. Cox proportional hazards regression models were used to assess the effects of SV metrics, immune-related indices, and clinicodemographic factors on overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR) differences were tested using the chi-square test, and immune parameters were compared using Wilcoxon rank-sum tests and correlation analyses.
Results: Multivariate analysis identified increased SV after CIT as an independent adverse prognostic factor for both OS (hazard ratio (HR) = 1.561, 95% confidence interval (CI), 1.193-2.041, p = 0.001) and PFS (HR = 1.411, 95% CI, 1.106-1.800, p = 0.006). Patients with increased SV exhibited significantly shorter OS and PFS and a lower ORR (all p < 0.005). Increased SV was also associated with markedly lower total, CD4+, and CD8+ TIL densities and, at the systemic level, lower absolute lymphocyte count (ALC), and higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) (all p < 0.0001), indicating both local and systemic immune suppression.
Conclusion: SV change reflects both local and systemic immune remodeling during CIT in ES-SCLC. As a noninvasive and measurable imaging biomarker, SV change holds translational potential for immune monitoring and treatment response assessment.

Keywords:  chemo-immunotherapy; extensive-stage small-cell lung cancer; immune-related parameter; spleen volume; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1177/17588359261417776
Nat Commun. 2026 Feb 17.

Phenotype of circulating tumor-reactive T cells predicts immune checkpoint inhibitor response in non-small cell lung cancer.

Katsuhiro Ito, Kei Iida, Tomoko Hirano, Merrin Man Long Leong, Kenji Morii, Toshi Menju, Hiroshi Date, Hiroaki Ozasa, Hironori Yoshida, Toyohiro Hirai, Shusuke Kawashima, Kazuhiro Aoyama, Yuka Saeki, Takashi Inozume, Takashi Kobayashi, Kenji Chamoto, Tomonori Yaguchi.

Peripheral blood (PB) is a source of tumor-infiltrating tumor-reactive T cells (TR-T). Circulating TR-Ts (cTR-T) in PB are expected to contribute to the efficacy of immune checkpoint inhibitors (ICIs), but their phenotype remains poorly understood. Here we analyse paired tumor-infiltrating and peripheral CD8+ T cells from patients with non-small cell lung carcinoma (NSCLC), using single-cell RNA and T cell receptor (TCR) sequencing. Tumor-infiltrating TR-Ts are defined based on the reported TR-T-associated gene signatures. Using their TCR sequence as a barcode, we identify cTR-Ts and their specific surface markers, including CD49a, CD49b, and HLA-DR. Trajectory analysis assigns a progenitor-like phenotype to cTR-Ts, suggesting a potential developmental relationship with tumor-infiltrating TR-Ts. By single-cell transcriptomic and flow cytometric analysis on an ICI-treated cohort we show that pre-treatment cTR-Ts in responders are characterized by a relatively low expression of exhaustion-related CD38. Following the first dose, cTR-Ts of responders transit towards a TCF7+ stem-like phenotype. Additionally, we validate cTR-T's phenotypic changes following PD-1 blockade therapy in mouse tumor models with artificial antigen. These findings suggest that the phenotypic state and transition of cTR-Ts may reflect their functional potential after tumor infiltration and are associated with therapeutic outcomes of ICIs.

DOI: https://doi.org/10.1038/s41467-026-69680-x
Nano Lett. 2026 Feb 19.

Strengthening Antisense Oligonucleotide-Mediated Anti-Tumor Immunity via Metal-Organic Framework Nanoparticles.

Julia A Nowak, Ezra Cho, Meredith A Davis, Siyi Zheng, Lauren Bell, Fanrui Sha, Julian S Magdalenski, Ashley Lui, Marco Napoli, Rana Falahat, James J Mulé, Elsa R Flores, Omar K Farha, Michelle H Teplensky.

  Tumor overexpression of programmed death-ligand one (PD-L1) inhibits immune recognition. Existing monoclonal antibodies are fragile and penetrate tumors poorly, leading to variable outcomes. Antisense oligonucleotides (ASOs) can reduce PD-L1 expression, but require frequent high dosing due to rapid degradation, clearance, and poor uptake. To overcome this, we harnessed metal-organic frameworks (MOFs) to protect and deliver ASOs, reducing PD-L1 expression and elevating downstream immunity. With various PD-L1-specific ASOs loaded into NU-1000 MOFs, we sustain release up to 7 days, reduce PD-L1 expression across triple negative breast cancer and melanoma, and stimulate dendritic cells to amplify T cell proliferation. This dual tumor and immune cell modulation via MOF-mediated ASO delivery increases tumor caspase-3 expression and killing of human melanoma with patient tumor-infiltrating lymphocytes, and elongates in vivo survival. This research highlights a strategy to utilize ASOs without sequence modifications and with a reduced dosing frequency, enabling broadly applicable oncogene-targeting oligonucleotide delivery.

Keywords:  Immunomodulation; antisense oligonucleotides; drug delivery; metal−organic frameworks; programmed-death ligand-1

DOI:  https://doi.org/10.1021/acs.nanolett.5c05579
Cancer Immunol Immunother. 2026 Feb 19. 75(3): 82

Microwave ablation combined with dendritic cells enhances CD8+ T cell activation in rechallenged tumor mouse model.

Ji Ma, Fengkuo Xu, Meixiang Wang, Shanlong Zhang, Jing Sang, Huanan Chen, Fu Wen, Ruiyang Ge, Qi Xie, Zhigang Wei, Xin Ye.

   OBJECTIVE: Microwave ablation (MWA) has shown favorable safety and efficacy in patients with non-small cell lung cancer (NSCLC). However, local recurrence remains a major concern that compromises long-term survival. Dysfunction of dendritic cells (DCs) constitutes a key immunosuppressive factor that limits effective T cell-mediated antitumor responses. To overcome this limitation, we evaluated the therapeutic potential of combining MWA with DC-based immunotherapy.
METHODS: A Lewis lung carcinoma (LLC) rechallenge mouse model was established to assess the efficacy of the combination of MWA and DC therapy in preventing post-ablation tumor recurrence. The immune landscape in tumors and tumor-draining lymph nodes (TdLNs) was analyzed by flow cytometry.
RESULTS: The combination of MWA and DC therapy markedly suppressed tumor recurrence and promoted potent antitumor immunity, as evidenced by an increased proportion and functional activation of CD8⁺ T cells in both recurrent tumors and TdLNs. In addition, the combination treatment substantially increased the frequency and immunostimulatory capacity of migratory type 1 conventional dendritic cells (Mig cDC1s) within TdLNs. These results indicate that cDC1s are crucial mediators of the enhanced antitumor response induced by MWA combined with DC therapy.
CONCLUSION: Our findings highlight a synergistic antitumor mechanism of MWA and DC-based therapy through cDC1 activation and CD8⁺ T cell enhancement, providing a promising strategy to reduce tumor recurrence after MWA.

Keywords:  CD8+ T cell; Combination therapy; DC-based therapy; Dendritic cells; Microwave ablation; Type 1 conventional dendritic cells

DOI:  https://doi.org/10.1007/s00262-026-04317-y
Biochim Biophys Acta Rev Cancer. 2026 Feb 13. pii: S0304-419X(26)00027-2. [Epub ahead of print]1881(2): 189555

SPP1 as a central mediator in the tumor microenvironment: Orchestrating cellular crosstalk, immune evasion, and therapy resistance.

Linhong Wang, Yachen Cheng, Jialu Li, Rulan Liao, Xiaohui Gao, Renle Du.

  Secreted phosphoprotein-1 (SPP1) is a multifaceted glycoprotein that extends beyond its role as a mere component of the extracellular matrix, functioning instead as a pivotal signaling hub within the tumor microenvironment (TME). This review synthesizes current evidence regarding how SPP1 orchestrates a complex cellular network by mediating bidirectional crosstalk between cancer cells and key stromal components including cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and lymphocytes. We elucidate how these interactions drive TME reprogramming, facilitating processes such as extracellular matrix remodeling, angiogenesis, immune evasion, and the establishment of therapeutic resistance to both chemotherapy and immunotherapy. Furthermore, we assess emerging therapeutic strategies targeting SPP1 such as aptamers and antibodies, highlighting their preclinical efficacy alongside the translational challenges that must be addressed. Ultimately, targeting the SPP1-mediated network represents a promising approach for dismantling the pro-tumorigenic TME and enhancing cancer treatment outcomes.

Keywords:  SPP1; Tumor microenvironment; Tumor-associated fibroblasts; Tumor-associated macrophages; Tumor-infiltrating lymphocytes; cancer therapy

DOI:  https://doi.org/10.1016/j.bbcan.2026.189555
Curr Res Transl Med. 2026 Feb 12. pii: S2452-3186(26)00004-8. [Epub ahead of print]74(1): 103567

Preclinical evidence of anti-CD19 CAR-T cell in vitro and in vivo efficacy against CD19-expressing acute myeloid leukemia.

Misa Eugene Norbert, Alexis Cuffel, Jérémie Martinet, Laetitia Jean, Clara Blondel, Justine Dehayes, Aurélie Bisson, Camille Giverne, Chrystel Marton, Ibrahim Yakoub-Agha, Monica L Guzman, Jean-Baptiste Latouche, Olivier Boyer.

   OBJECTIVE: Chimeric antigen receptor-modified T cell (CAR-T) therapy has demonstrated remarkable efficacy against refractory B-cell malignancies. This approach is more challenging in non-B-cell hematological malignancies such as acute myeloid leukemia (AML), especially because of target antigen selection difficulty and putative endogenous tumor cell resistance. Nonetheless, some AMLs express CD19, making them potential candidates for anti-CD19 CAR-T (CART19) therapy. This study aimed at establishing preclinical evidence supporting the therapeutic potential of academically developed CART19 cells for the treatment of CD19⁺AMLs.
METHODS: Luciferase+/Green Fluorescent Protein+AML-derived Molm-13 cells were transduced with gammaretroviral vectors to express CD19 (Molm-13-CD19), turning them into potential AML targets for CART19, generated from healthy donor T lymphocytes after lentiviral vector transduction. These CD19+AML cells could be used in vitro for assessing CART19 specific cytotoxic capacity and in vivo for evaluating CART19 anti-tumor efficacy in immunodeficient mice.
RESULTS: In vitro, flow cytometry-based cytotoxicity assays evidenced CART19 potent specific killing of Molm-13-CD19 cells, up to 75% at a 2.5:1 effector-to-target ratio after 16 h of coculture. In vivo, CART19 significantly prolonged survival of immunodeficient mice bearing Molm-13-CD19-derived tumors by efficiently killing AML cells, as assessed by bioluminescence imaging. Moreover, in immunodeficient mice lacking MHC to limit graft-versus-host disease, CART19 persisted in bone marrow and spleen up to 90 days post-treatment as evidenced by flow cytometry.
CONCLUSION: These findings demonstrated CART19 efficacy against CD19+AML and allowed us to set up a clinical trial which is ongoing (NCT06649227), based on the injection of academically-produced CART19 in strictly selected patients with relapsed/refractory CD19+AML.

Keywords:  Acute myeloid leukemia; Anti-CD19 CAR-T; CAR-T; CD19; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.retram.2026.103567
Cancer Immunol Res. 2026 Feb 20.

Baseline tumor features and systemic immune dynamics underlying efficacy in MSS metastatic colorectal cancer treated with regorafenib, ipilimumab, and nivolumab.

Jian Ye, Chongkai Wang, Colt A Egelston, Weihua Guo, Rifat Mannan, Peter P Lee, Marwan G Fakih.

Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies. In a phase I trial, we observed encouraging efficacy of the combination of regorafenib, ipilimumab, and nivolumab (RIN), with a 27.6% overall response rate and a median overall survival of 20 months. The most pronounced benefits were observed in patients without liver metastases. To uncover immunological mechanisms underlying response and resistance, we performed correlative studies of the tumor microenvironment (TME) and systemic immune features. Tumor biopsies from eight patients and peripheral blood samples from 29 patients with MSS mCRC were collected and analyzed at baseline and during treatment. At baseline, tumors from good responders exhibited enhanced proliferation, DNA repair pathways, and STING expression, while poor responders showed enrichment of complement and metabolism pathways. In peripheral blood, good responders had a higher CD4/CD8 T cell ratio, increased dendritic cells, and intact type 1 cytokine responses. In contrast, poor responders exhibited more effector T cell differentiation, elevated immune checkpoint molecule expression, and increased DNA damage in lymphocytes. In good responders, RIN therapy increased tumor-infiltrating lymphocytes and upregulated immune activation genes, accompanied by heightened T cell proliferation and activation in peripheral blood, including expansion of low-frequency TCR clones in CD8⁺ T cells. Patients with liver metastases exhibited T cell senescence and metabolic hyperactivation, correlating with therapeutic resistance. These findings highlight that pre-existing tumor immunogenicity and T cell functional capacity are associated with response to RIN therapy, and that RIN treatment may facilitate both systemic T cell activation and local TME modulation.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0243
Nat Commun. 2026 Feb 17.

Adoptive γδ T cell therapy controls cytomegalovirus infection in preclinical transplantation models.

Gabriel Marsères, Coline Gentil, Claire Tinevez, Maxime Courant, Anaïs Cosentino, Selma Cornillot-Clément, Victor Bigot, Vincent Pitard, Atika Zouine, Julien Izotte, Isabelle Garrigue, Valérie Prouzet-Mauleon, Béatrice Turcq, Dany Anglicheau, Edouard Forcade, Hannah Kaminski, Bruno Silva-Santos, Pierre Merville, Myriam Capone, Julie Déchanet-Merville, Lionel Couzi.

γδ T cells show promise for anti-tumoral therapies but have yet to be evaluated to treat infectious diseases. In this preclinical study, we assess a Vδ1 + γδ T cell-based adoptive cell therapy, named Delta One T cells, to treat cytomegalovirus (CMV) infection in high-risk transplant recipients. Even when expanded from CMV-naïve healthy donors, Delta One T cells efficiently control CMV dissemination in vitro. CMV recognition is independent of the γδTCR but requires LFA-1 co-stimulation. In an in vivo model, adoptive transfer of mouse γδ T cells recapitulating Delta One T cell features protects mice against lethal murine CMV infection. Importantly, CMV-reactive Delta One T cells can be successfully generated from kidney transplant recipients undergoing refractory CMV infections and maintain their functionality in the presence of immunosuppressive drugs. These findings broaden the scope of γδ T cell therapies to infectious diseases and uncover a universal adoptive T cell therapy to treat refractory CMV infections.

DOI: https://doi.org/10.1038/s41467-026-69538-2
J Immunother Cancer. 2026 Feb 18. pii: e013665. [Epub ahead of print]14(2):

Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.

Heydar Moravej, Taha Rakhshandehroo, Radia M M Khan, Victoria Marie Rivet, Elodie Marcandalli, Shreya R Mantri, Pegah Taklifi, Uk-Jae Lee, Benjamin B V Louis, Leila A Munaretto, Kathryn Regan, Zoe Farkash, Lea Berland, Zeina Gabr, Alexandra N Wolff, Antonia Kowalewski, Harris H Allen, Ali Nili, Jessika Baral, Dayna Mercadante, Mariateresa Fulciniti, Caron A Jacobson, Adam S Sperling, Omar Nadeem, Hadi T Nia, Michael Hemann, Nikhil C Munshi, Mohammad Rashidian.

   BACKGROUND: Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T persistence and function. It remained unclear whether CAR-Es are effective across distinct tumor contexts, when using patient-derived T cells, or in preventing exhaustion and sustaining persistence. It was also unknown whether CAR-Es can selectively expand CAR-Ts in humanized mice with pre-existing T cells, and to what extent their efficacy depends on IL-2Rβγ vs IL-2Rα engagement. While IL-2Rα (CD25) has been classically linked to potent antitumor responses and memory formation, it also drives IL-2-associated toxicities, including vascular leak and preferential regulatory T cell expansion.
METHODS: We systematically dissected CAR-E signaling requirements by engineering IL-2 variants with selective receptor affinities. Multiple CAR-E constructs were developed and tested across a range of in vitro and in vivo models.
RESULTS: We demonstrate that CAR-E activity is entirely independent of IL-2Rα and critically dependent on IL-2Rβγ signaling. A next-generation IL-2Rα-sparing CAR-E maintained full potency, driving robust CAR-T expansion, persistence, and tumor clearance, even at low doses and when using CAR-T cells derived from previously treated multiple myeloma patients. These CAR-T cells not only resisted exhaustion but also re-expanded months later to eradicate tumor rechallenges. In humanized mice with pre-established T cells, CAR-Es selectively expanded CAR-Ts to dominate the circulating T-cell pool. CAR-E exerted a dominant influence on CAR-T fate, overriding tumor-derived cues and enforcing consistent phenotypes across diverse preclinical models.
CONCLUSIONS: These findings nominate a lead B-cell maturation antigen (BCMA)-IL-2 CAR-E candidate with strong translational potential for clinical development and establish IL-2Rβγ as a key driver of CAR-E activity. The results also identify IL-2Rα as dispensable and provide a mechanistic framework for designing safer, IL-2Rα-sparing CAR-Es.

Keywords:  Chimeric antigen receptor - CAR; Cytokine; Multiple Myeloma

DOI:  https://doi.org/10.1136/jitc-2025-013665
Br J Pharmacol. 2026 Feb 19.

Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives.

Natsumi Imano, Mikako Nishida, Miho Tokumasu, Weiyang Zhao, Nahoko Yamashita, Heiichiro Udono.

   BACKGROUND AND PURPOSE: Ascochlorin (ASC) is an antiviral antibiotic from the fermented broth of Ascochyta viciae which exerts an inhibitory effect to cancers. Its impact on immune cells has not been examined. In this study, we obtained ASC derivatives with less cytotoxicity and determined whether they affected T cells, indicating possible immune-mediated antitumour effects.
EXPERIMENTAL APPROACH: Newly synthesised ASC derivatives were screened for inhibitory effects on T-cell antigen receptor (TCR)-stimulated proliferative responses using murine CD4+ and CD8+ T cells. Two compounds were identified that exhibited >10-fold less toxicity compared with ASC. N184, the less toxic of the two, was analysed for its in vivo antitumour effects, and in vitro effects on CD8+ T-cell proliferation, survival, cytokine production and exhaustion, using microscopy, qPCR and flow cytometry.
KEY RESULTS: N184 induced limited IL-9 production in CD8+ T cells following TCR stimulation, thereby improving cell survival. It also enhanced cytokine production in the late phase of proliferation and suppressed the induction of exhaustion. N184 suppressed tumour growth in mice in a CD8+ T cell-dependent manner. The effect was partially prevented by an IL-9-neutralising antibody.
CONCLUSION AND IMPLICATIONS: N184 induces differentiation of IL-9-producing CD8+ T cells in vitro and elicits antitumour immunity in an IL-9-dependent manner.

Keywords:  CD8 positive T lymphocytes; IFN‐γ; Tc9; ascochlorin derivative; cell survival; interleukin‐9; tumour immunity

DOI:  https://doi.org/10.1111/bph.70316
Cancer Res Commun. 2026 Feb 19.

Collagen-bearing exosomes from breast cancer-associated fibroblasts promote T cell dysfunction.

Samir Jana, Matthew Lawton, Pin-Ji Lei, Harold Hui, Andrew Emili, Dennis Jones.

Cancer-associated fibroblasts (CAFs), a major component of the breast tumor microenvironment, drive immune evasion in various cancers by promoting T cell exclusion and dampening T cell activation. Previous studies have implicated CAF-derived soluble factors in mediating these immunosuppressive effects. Here, we investigated whether exosomes secreted by CAFs could suppress T cell activity. Inhibition of global exosome secretion in breast tumor-bearing mice significantly reduced tumor growth and increased tumor-infiltrating T cells with lower exhaustion marker expression. Conversely, administration of CAF-derived exosomes into tumors produced the opposite effects. Moreover, CAF exosomes associated with T cells in vivo and impaired T cell activation and cytotoxic potential in ex vivo assays. Proteomic and biochemical analyses of T cells exposed to CAF exosomes revealed dampened early T cell receptor signaling. Mass spectrometry identified an extracellular matrix signature on CAF exosomes. Depleting Type I and Type V collagens from CAF exosomes restored T cell proliferation, while overexpression of collagen in cancer cells led to its incorporation into exosomes, which suppressed T cell activation. These findings suggest that a signaling bridge between CAF exosomes and T cells, mediated by collagen, promotes T cell dysfunction, contributing to immune evasion in breast cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0259
Am J Clin Oncol. 2026 Feb 17.

Relevance of Chemokines in Mobilizing γδ T Cells in the Biliary Tract Cancer Microenvironment: Potential for γδ T-Cell-Based Adoptive Cell Therapy.

Saikat Mandal, Arkadeep Dhali, Manideepa Maji, Guruprasad Aithal.

   OBJECTIVE: Biliary tract cancer (BTC) has a poor prognosis with limited therapeutic options. γδ T cells represent an MHC-independent immune cell population; however, their therapeutic efficacy in solid tumors is constrained by insufficient tumor infiltration. Chemokine-mediated trafficking is fundamental to T lymphocyte recruitment; however, the chemokine landscape of the BTC tumor microenvironment (TME) remains uncharacterized. Using single-cell RNA sequencing of BTC tissues, we delineated chemokine ligand expression patterns, stratified chemokine producers by lineage, assessed γδ T-cell recruitment mechanisms, and identified chemokine-mediated immune escape.
METHODS: We analyzed single-cell RNA sequencing data from 3 independent GEO cohorts (GSE210066, GSE201425, and GSE213452; 19 patients) to comprehensively delineate γδ T-cell mobilization-related chemokine expression across the BTC TME using the Seurat v5.0 pipeline in R.
RESULTS: Analysis identified a multiaxis chemokine profile within the BTC TME. High expression of CCL5, CCL4, and CCL3 established predominant CCR5-mediated recruitment axes supporting Vγ9Vδ2 T-cell infiltration, whereas CCL2 and modest CXCL8 supported CCR2+ and CXCR1+ Vδ1 T-cell recruitment. Notably, CXCL16 expression supported epithelial γδ T-cell homing through CXCR6. However, critical deficiencies in CXCL9 and CXCL10 suppress the IFN-γ-driven immunity. Paradoxically, chemokine axes supporting γδ T-cell recruitment (CCL2-CCR2, CXCL8-CXCR1, CXCL12-CXCR4) simultaneously recruit immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs).
CONCLUSION: Comprehensive single-cell analysis identified selective chemokine recruitment signatures supporting γδ T-cell infiltration but revealed paradoxical corecruitment of immunosuppressive populations. Patient stratification through chemokine profiling, combined with γδ T-cell enrichment and targeted chemokine antagonism, represents a rational therapeutic strategy.

Keywords:  adoptive cell therapy; biliary tract cancer; chemokines; cholangiocarcinoma; gallbladder cancer; γδ T-cell

DOI:  https://doi.org/10.1097/COC.0000000000001306
Theranostics. 2026 ;16(8): 4245-4259

CAR-T manufacturing reduces heterogeneity between CIDP and multiple myeloma patient-derived T cells.

Xu Wang, Pu Wang, Qi Zhou, Xianzheng Wei, Yuhang Jin, Ying Liao, Xuan Zhao, Rui Hou, Sijin Li, Zhangchun Guan, Wen Ma, Dan Liu, Ming Shi.

  Rationale: CAR-T cell therapy has demonstrated remarkable promise for managing specific autoimmune disorders. However, it remains unclear, whether long-term immunosuppressive therapy in autoimmune patients adversely affects the phenotype and function of patient-derived CAR-T products. This study aimed to compare the characteristics of T cells and manufactured CAR-T cells from patients with multiple myeloma (MM) and chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: T cells isolated from MM and CIDP patients, as well as healthy volunteers (for baseline comparisons only), were analyzed. CAR-T cells were generated using an identical manufacturing process. A comprehensive analysis was conducted, including flow cytometry for phenotypic and functional assessment, transcriptomic profiling via RNA sequencing, and in vitro functional assays such as cytokine secretion and cytotoxicity tests. Results: T cells from CIDP patients showed phenotypes and functional profiles more comparable to those from healthy volunteers. In contrast, MM-derived T cells showed increased CD8⁺ T cell frequency, elevated exhaustion markers, reduced naïve and less-differentiated subsets, and enhanced effector molecule production upon non-specific stimulation. CAR-T manufacturing reduced these inherent differences, yielding similar differentiation states, transcriptomic profiles, and convergent cytotoxic capacities. However, distinct immunomodulatory features persisted, as CIDP-derived CAR-T cells displayed reduced activation markers and lower IFN-γ secretion upon antigen stimulation compared to MM-derived CAR-T cells. Conclusions: Our study reveals that CAR-T manufacturing process can reduce pre-existing T-cell heterogeneity across different patient populations. These findings support the feasibility of autologous CAR-T therapies in immunosuppressed autoimmune patients, demonstrating that critical cytolytic functions are preserved despite residual alterations in cytokine profiles.

Keywords:  CAR-T cell therapy; CIDP; MM; T cell heterogeneity; autoimmune diseases; transcriptomic reprogramming

DOI:  https://doi.org/10.7150/thno.125983
Acta Biomater. 2026 Feb 12. pii: S1742-7061(26)00091-7. [Epub ahead of print]

Visible tumor-targeting biohybrid vehicles reprogram cancer-associated fibroblasts to potentiate photothermal immunotherapy.

Limin Jin, Xiaohan Yang, Yan Zhang, Xin Meng, Pengyu Huang, Lin Mei, Dunwan Zhu, Xia Dong, Feng Lv.

  The extracellular matrix (ECM) is a physical barrier that severely hinders the deep penetration of photothermal agents and immune cells, which is a major challenge to the efficacy of tumor photothermal immunotherapy. In this study, a visible tumor-targeting platelet membrane-wrapped biohybrid vehicle was developed to potentiate photothermalimmunotherapy through cancer-associated fibroblasts (CAFs) reprogramming. This system integrated IR820-modified platelet membrane and manganese-polyphenol nanoparticlesloaded with losartan. Based on the image contrast signals from IR820 and manganese ions, the biohybrid system enabled visual delivery under the guidance of fluorescence-magnetic dual-modal imaging. After reprogramming CAFs to a quiescent state with released losartan, the ECM was remodeled. The attenuated physical barrier and platelet carriers collectively facilitated the deep penetration of photothermal agents, improving the sensitivity of photothermal therapy. Moreover, the synergistic strategy of photothermal stimulation and CAFs regulation simultaneously activated the systemic immunity and alleviated the immunosuppressive tumor microenvironment. The biohybrid delivery system effectively reconstructed the anti-tumor immune defense system to boost the efficacy of photothermal immunotherapy through a positive feedback mechanism. STATEMENT OF SIGNIFICANCE: The dense extracellular matrix (ECM) constitutes a major physical barrier that severely restricts the penetration of photothermal agents and immune cells into tumors, thereby substantially limiting the efficacy of photothermal immunotherapy. A key cause of this barrier is cancer-associated fibroblasts (CAFs), which also suppress immunity. Reverting CAFs to a quiescent state or reprogramming them toward a tumor-suppressive phenotype offers a promising strategy to ameliorate ECM deposition and reverse immunosuppression. A visible tumor-targeting platelet membrane-wrapped biohybrid vehicle was developed to potentiate photothermal-immunotherapy through CAFs reprogramming. This intervention disrupts the stromal barrier and mitigates immune suppression for boosting anti-tumor immunity. Furthermore, the system enables real-time, dual-modal MRI-fluorescence imaging, providing a visual guidance platform for precision photothermal immunotherapy.

Keywords:  Biohybrid system; Cancer-associated fibroblasts; Imaging guidance; Photothermal immunotherapy; Targeted delivery

DOI:  https://doi.org/10.1016/j.actbio.2026.02.018
Sci Adv. 2026 Feb 20. 12(8): eaea2511

KRASG12V/HLA-A*02:01-targeted chimeric antigen receptor T cells exhibit potent preclinical activity against solid tumors.

Huimin Shao, Fei Xu, Jiangyue Xu, Lingjie Zhou, Yao Wu, Lianjun He, Xueyi Qian, Weijie He, Nanlin Jiao, Yabin Xia, Jun Zhao, Lili Sheng, Guoliang Mao, Tao Ma, Wei Wang, Shaoxiang Luo, Li Fu, Zhenyu Xu.

Despite advances in chimeric antigen receptor T cell (CAR T cell) therapy for leukemia and lymphoma, solid tumors remain challenging because of limited target specificity and safety concerns. Neoantigens like KRASG12V, a highly prevalent yet undruggable mutation in solid tumors, offer tumor-exclusive specificity. This study developed CAR T cells targeting KRASG12V/HLA-A*02:01 using phage antibody display to identify high-affinity single-chain variable fragments. Engineered B9 CAR T cells specifically lysed tumor cells and patient-derived cancer organoids expressing KRASG12V/HLA-A*02:01, demonstrating potent antitumor activity. Animal studies showed that B9 CAR T cells effectively controlled tumor growth in subcutaneous pancreatic ductal adenocarcinoma (PDAC) xenografts, as well as in metastatic and peritoneal PDAC models. Safety assessments in NCG-HLA-A2.1 and C57BL/6 mice revealed no detectable in vivo toxicity, supporting the clinical applicability of B9 CAR T cells. Collectively, our neoantigen-targeted CAR T cell therapy against solid tumors shows great potential for future clinical trials in patients with KRASG12V/HLA-A*02:01, paving the way for clinical translation.

DOI: https://doi.org/10.1126/sciadv.aea2511
Int Immunol. 2026 Feb 17. pii: dxag009. [Epub ahead of print]

Transduction of Batf family members provides distinct functions to mouse CD8+ T cells.

Kenta Kondo, Mina Kumode, Hiroki Satooka, Koji Terada, Yusuke Sano, Nobuhito Nitta, Daisuke Okuzaki, Kensuke Takada, Takako Hirata, Hidetaka Kosako, Akira Andoh, Makoto Murata, Yasutoshi Agata.

  Members of the Batf family, including Batf, Batf2, and Batf3, play critical roles in various immune cell types. Several studies have suggested redundant functions, as they can compensate for each other's functions. Here, we show that transduction of Batf family members confers distinct functional characteristics on CD8+ T cells. Batf- and Batf2-transduced CD8+ T cells exhibited effector and memory-like phenotypes, respectively. Notably, Batf3-transduced CD8+ T cells showed both effector- and memory-like phenotypes in response to effector- and memory-associated cytokines, respectively, and superior anti-tumor activity in vivo among Batf family members. Our results demonstrated that each Batf family member has distinct functions in CD8+ T cells. These findings help us understand the roles of the Batf family members in CD8+ T cells and contribute to the development of optimized adoptive T cell therapies against cancer.

Keywords:  infection; tumor immunity

DOI:  https://doi.org/10.1093/intimm/dxag009