bims-tuinly 2026-03-08 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–03–08
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Expansion of IL-2-independent tumor-infiltrating lymphocytes through a feeder-free process: a preclinical study for solid tumors.
GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion.
A high density of T-cell lymphocytes and Tregs subset correlate to a worse survival in major salivary gland carcinomas.
Immune Network Construction and Prognostic Evaluation of Checkpoint Genes in Endometrial Cancer Using STRING, MCODE, and GEPIA2.
Increased Infiltration of CD4+, CD8+, and CD68+ Cells at the Invasive Front Is Associated With Favorable Prognosis in Obstructive Colorectal Cancer: A Retrospective Observational Study.
A Dual-Metabolic NIR-II Probe for In Vivo Imaging of Tumor-Infiltrating Lymphocytes.
Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.
Pre-existing TCR clones drive major pathological responses in HNSCC patients treated with dual immune checkpoint inhibitors.
Clinicopathological Predictors of Recurrence in High-Risk Basal Cell Carcinoma Patients, A Retrospective Analysis.
Potential Immune Microenvironment Biomarkers in SCLC: J-TAIL-2 Observational Study.
Nanomedicine Meets Immunotherapy: Advancing Adoptive Cell Therapy with Nanoparticles in the Treatment of Cancer with Sustainability Perspectives.
P16+ Cells Drive Adverse Postischemic Cardiac Remodeling Through CCL8-Mediated Recruitment of Cytotoxic Lymphocytes.
CLDN18.2 in lung adenocarcinoma as a promising target of chimeric antigen receptor T cells.
Investigating PAK inhibition in combination with PD-1 blockade to enhance cytotoxic CD8+ T cell-mediated killing and suppress invasion of ovarian cancer cells.
CAR-NKT cell therapy for tumors: promise and progress.

Cancer Biol Med. 2026 Mar 05. pii: j.issn.2095-3941.2025.0441. [Epub ahead of print]

Expansion of IL-2-independent tumor-infiltrating lymphocytes through a feeder-free process: a preclinical study for solid tumors.

Ying Zhang, Sicheng Du, Rongrui Liu, Chuanhua Zhao, Juan Li, Sisi Ye, Man Zhang, Xingming Ma, Zhou He, Wenjia Zhuang, Huajun Jin, Jianming Xu.

   OBJECTIVE: Conventional tumor-infiltrating lymphocyte (TIL) therapy for solid tumors relies on high-dose interleukin-2 (IL-2) during expansion and post-infusion, and promotes T-cell exhaustion and toxicity. Herein, we developed a feeder-free, low-dose IL-2 TIL expansion protocol and evaluated whether hydroxychloroquine (HCQ) or programmed cell death protein 1 (PD-1) blockade might enhance therapeutic efficacy and decrease IL-2 dependence.
METHODS: TILs from multiple solid tumors were expanded ex vivo with decreased-dose IL-2, IL-7, and IL-15 plus CD3/CD28 co-stimulation, without feeder cells. TIL products were assessed via quality control, T-cell phenotypes, and exhaustion markers. Cytotoxic activity was measured in vitro through interferon-gamma (IFN-γ) release and real-time cell analysis (RTCA). HCQ-induced changes in major histocompatibility complex class I (MHC-I) and programmed death-ligand 1 (PD-L1) expression were assessed in tumor cell lines, and RTCA-based cytotoxicity was evaluated using T-cell receptor-engineered T cells (TCR-T cells). The in vivo efficacy of HCQ and PD-1 blockade separately combined with TIL therapy was examined in a colorectal cancer patient-derived xenograft (PDX) model.
RESULTS: The protocol consistently produced viable TILs of favorable quality across tumor types, with variable CD8+ and memory T-cell profiles. Expanded TILs showed effector-to-target (E:T) ratio-dependent tumor cell killing in RTCA and secreted IFN-γ across multiple tumor types. HCQ significantly upregulated MHC-I expression in vitro (P < 0.05) without affecting PD-L1 expression or impairing TIL proliferation, and enhanced early TCR-T-mediated killing. In the PDX model, TIL plus HCQ, compared with TIL, showed less tumor growth and greater MHC-I expression, although these differences were not significant, given the small sample size. TIL plus low-dose PD-1 blockade significantly reduced tumor volume versus the control group (P = 0.002) and maintained higher body weights than the TIL-only and control groups.
CONCLUSIONS: The feasibility of a feeder-free, low-dose IL-2 TIL expansion system was demonstrated. PD-1 blockade significantly enhanced antitumor activity and treatment tolerability, thus supporting its promise as an alternative to high-dose IL-2. HCQ demonstrated potential immunomodulatory effects, although its in vivo benefit was minimal. This strategy warrants further clinical evaluation in solid tumors.

Keywords:  MHC class I; PD-1 blockade; Tumor-infiltrating lymphocytes; hydroxychloroquine; solid tumors

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0441
Oncogene. 2026 Mar 04.

GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion.

Jiayi Zhou, Yinggui Yang, Ran Ye, Jiani Lin, Huiyi Feng, Xiaojuan Pei, Mingzhen Li, Jiangfan Peng, Xinzhi Yang, Peter Yat Ming Woo, Danny Tat Ming Chan, Penghui Zhou, Jie Mao, Zhuohao Liu, Dinglan Wu.

Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8+ TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by TNFRSF18) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8+ TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8+ TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8+ TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.

DOI: https://doi.org/10.1038/s41388-026-03705-z
Sci Rep. 2026 Mar 03.

A high density of T-cell lymphocytes and Tregs subset correlate to a worse survival in major salivary gland carcinomas.

Debora Anconelli, Francesco Vasuri, Luca Novelli, Luca Saragoni, Luca Messerini, Calogero Saieva, Elena Cantone, Luca Muscatello, Guido Bartoletti, Elena Niccolai, Amedeo Amedei, Alessandro Franchi, Maria Raffaella Ambrosio.

  Salivary gland carcinomas (SGC) are rare and heterogeneous tumors with limited therapeutic options in advanced stages. Recent evidence suggests a potential role of the tumor immune microenvironment (TME) in disease progression. This study aimed to investigate the immune profile of SGCs by analyzing tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and PD-L1 expression, and to assess their correlation with histological grade and clinical outcome. A retrospective analysis was conducted on 103 SGC cases. Immunohistochemistry for CD3, CD4, CD8, CD20, CD56, PD-1, PD-L1, FOXP3, CD68, and CD163 was performed. Digital slide analysis was carried out in intratumoral and peritumoral regions using QuPath software. High intratumoral FOXP3 + Tregs were significantly associated with high-grade tumors and worse progression-free survival (PFS) (p = 0.009). A higher peritumoral CD3 + T cell density correlated with poor prognosis (p = 0.046). Concordance between pathologist assessments and QuPath quantification was moderate to high (Cohen's K = 0.71). In conclusion, intratumoral Tregs and peritumoural T lymphocytes may be used as negative prognostic biomarkers. Future multicentric studies and AI (Artificial Intelligence)-driven analyses could enhance immune characterization and guide immunotherapeutic strategies in SGC.

Keywords:  Artificial intelligence; Immunohistochemistry; Salivary gland carcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-026-39357-y
Cancer Diagn Progn. 2026 Mar-Apr;6(2):6(2): 335-349

Immune Network Construction and Prognostic Evaluation of Checkpoint Genes in Endometrial Cancer Using STRING, MCODE, and GEPIA2.

Rafael Everton Assunção Ribeiro DA Costa, Luiz Carlos Zeferino, Júlio César Teixeira.

   Background/Aim: Endometrial cancer (EC) is an important health issue among women, with immunotherapy emerging as a promising option for advanced cases. Tumor-infiltrating lymphocytes (TILs) and immune checkpoints, including PDCD1, CD274, and PDCD1LG2, are increasingly recognized as prognostic markers. This study aimed to construct an in silico immune network and assess the prognostic impact of checkpoint genes in EC using STRING, MCODE, and GEPIA2.
Materials and Methods: Retrospective analysis used TCGA-UCEC (The Cancer Genome Atlas - Uterine Corpus Endometrial Carcinoma) and GTEx datasets and reported immune-related genes. Genes were analyzed in STRING v12.0 (confidence ≥0.7; up to 10 neighbors per node) to generate a protein-protein interaction (PPI) network, exported to Cytoscape v3.10.2, and processed with MCODE to identify functional clusters. Hub genes were evaluated for expression and overall survival (OS) in GEPIA2 using median-based stratification and log-rank tests (p<0.05). Six immune signatures were assessed in TIMER2.0. PDCD1 and CD274 showed strong interactions with other immune effectors.
Results: CD40 and LGALS9 were down- and upregulated, respectively, without affecting OS. Combined overexpression of CTLA4, PDCD1, TIGIT, CD8A, CD8B, GZMB, PRF1, TBX21, FOXP3, CXCL9, CD28, and ICOS correlated with improved OS, suggesting direct immune effects and enhanced responses to targeted therapies.
Conclusion: This in silico immune network highlights checkpoint centered hubs and coordinated immune programs with prognostic relevance in endometrial cancer, providing a rationale for biomarker guided immunotherapy development and patient stratification. Validation in independent cohorts and correlation with clinicopathologic and treatment response data are needed to support clinical translation.

Keywords:  Immune system phenomena; computer simulation; endometrial neoplasms; medical informatics applications; prognosis; regulator genes

DOI:  https://doi.org/10.21873/cdp.10532
Cancer Rep (Hoboken). 2026 Mar;9(3): e70508

Increased Infiltration of CD4+, CD8+, and CD68+ Cells at the Invasive Front Is Associated With Favorable Prognosis in Obstructive Colorectal Cancer: A Retrospective Observational Study.

Goro Takahashi, Seiichi Shinji, Toshiyuki Ishiwata, Takeshi Yamada, Kay Uehara, Akihisa Matsuda, Tomio Arai, Ryuji Ohashi, Yasuyuki Yokoyama, Takuma Iwai, Hiroshi Yoshida.

   BACKGROUND: Obstructive colorectal cancer (OCRC) presents as an oncologic emergency with poor prognosis. Although tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) are known to affect colorectal cancer outcomes, their roles in OCRC remain unclear.
METHODS AND RESULTS: We retrospectively analyzed 66 patients with Stages II-III OCRC who underwent curative resection following endoscopic decompression. CD4+, CD8+, and CD68+ cell densities at the tumor center and invasive front were quantified using multiplex immunofluorescence imaging. Cancer-specific survival (CSS) was assessed in relation to immune cell infiltration. Target immune cells were significantly more abundant at the invasive front compared to the tumor center. High densities of CD4+ TILs and CD68+ TAMs at the invasive front were associated with superior CSS (p = 0.0079 and p = 0.0088, respectively). Total immune cell density-defined as the sum of CD4+, CD8+, and CD68+ cells/mm2-was the strongest independent prognostic factor (HR = 30.8, p < 0.001).
CONCLUSIONS: High immune cell infiltration at the invasive front was associated with favorable prognosis, even in OCRC. As the invasive front represents the interface between host and tumor, assessment of the tumor immune microenvironment at this site may refine risk stratification and optimize clinical management in OCRC patients.

Keywords:  immunofluorescence; obstructive colorectal cancer; tumor microenvironment; tumor‐associated macrophages; tumor‐infiltrating lymphocytes

DOI:  https://doi.org/10.1002/cnr2.70508
Adv Healthc Mater. 2026 Mar 06. e05668

A Dual-Metabolic NIR-II Probe for In Vivo Imaging of Tumor-Infiltrating Lymphocytes.

Yike Cai, Rui Li, Yan Peng, Xiaolong Zhang, Ming Wu, Naishun Liao, Rui Zeng, Yongyi Zeng, Xiaolong Liu, Yao Huang, Yupeng Sun.

  Indocyanine green (ICG) is one of the few FDA-approved near-infrared (NIR) imaging probes, and its NIR-II off-peak emission shows clinical potential for medical imaging. However, its low brightness, short half-life, and lack of targeting specificity significantly limit broader clinical applications. Herein, we report a NIR fluorescent probe, ICG@Apt-PD1, for the preclinical in vivo imaging of tumor-infiltrating lymphocytes (TILs). This probe was synthesized by covalently conjugating a derivative of ICG to the pendant sulfhydryl group of a PD1-targeting aptamer (Apt-PD1). ICG@Apt-PD1 possesses an extended plasma half-life, high biocompatibility, and is metabolized via both hepatic and renal pathways, allowing for rapid clearance and reduced potential toxicity. Owing to its high brightness, photostability, and excellent tissue penetration, the probe enables high-quality NIR-II imaging of lymph nodes and permits the identification of inflammatory foci within a specific post-injection time window. Moreover, the probe achieves specific targeting of TILs through interaction with PD-1 receptors, thereby showcasing its strong potential for non-invasive in vivo imaging of TILs. Consequently, ICG@Apt-PD1 holds considerable promise for clinical translation in NIR-II imaging of lymph nodes, inflammatory foci, and TILs.

Keywords:  NIR‐II fluorescence probe; PD1‐targeting aptamer; dual‐metabolic; indocyanine green; tumor infiltrating lymphocyte

DOI:  https://doi.org/10.1002/adhm.202505668
Cell Rep Med. 2026 Feb 27. pii: S2666-3791(26)00049-2. [Epub ahead of print] 102632

Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.

Aleksandra Georgievski, Noémie Blanc, Mélanie Bruchard, Cassandre Pignol, Pierre-Simon Bellaye, Carmen Garrido, Ronan Quéré.

  We develop valrubicin-loaded immunoliposomes (Val-ILs), a nanoparticle-based therapy designed to target immunosuppressive cells that promote immune evasion in cancer. In vivo screening following intravenous administration in mice identifies nine relevant surface targets, including known immunoregulatory markers (LAG-3 and VEGFR2) and not-well-characterized candidates (CD11b, CD64, TIM1, CD200R3, CD204, CD49b, and SIGLEC-F). Within the tumor microenvironment, Val-ILs treatment broadly reduces the expression of these antigens on immunosuppressive populations, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and T helper 17 cells, as well as on innate anti-tumor cells such as tumor-associated natural killer cells and tumor-infiltrating dendritic cells. Across four murine cancer models, two responsive (T and B lymphomas) and two resistant (orthotopic breast and lung cancers), Val-ILs decorated with antibodies against the nine targets significantly enhance anti-PD-1 efficacy. This combination boosts the presence of CD4+ and CD8+ tumor-infiltrating lymphocytes, reprograms tumor-associated macrophages toward an M1-like phenotype, and improves tumor control and metastasis reduction.

Keywords:  enhance anti-tumor immunity in resistant cancer models; immunosuppressive cells; murine cancer models; nanoparticle-based therapy; reduced metastasis; tumor regression; valrubicin-loaded immunoliposomes

DOI:  https://doi.org/10.1016/j.xcrm.2026.102632
Clin Cancer Res. 2026 Mar 05.

Pre-existing TCR clones drive major pathological responses in HNSCC patients treated with dual immune checkpoint inhibitors.

Huaibin Ge, Housaiyin Li, Aditi Kulkarni, Zhangguo Chen, Pragati Upadhyay, Robert L Ferris, Jing H Wang.

PURPOSE: Immune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.
EXPERIMENTAL DESIGN: We analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.
RESULTS: Contrary to "clonal replacement" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of "super-expanded" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was "uncoupled" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.
CONCLUSIONS: Dual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-3749
Int J Surg Pathol. 2026 Mar 03. 10668969261419047

Clinicopathological Predictors of Recurrence in High-Risk Basal Cell Carcinoma Patients, A Retrospective Analysis.

Nora Abdelhafiz, Abdallah H Mohamed, Mohamed Hussein Mahran, Christeen N B Shaheed, Ola M Omran, Saeed A Al-Qahtania, Amal A Alqahtani, Ahmed Sohaib, Mohammed Abdoh Athlawi, Ahmed Mahran Shafiq, Ahmed Magdy, Alshaymaa Abdelghaffar, Rania A Herdan, Nahla Babiker, Enshrah Modathir Elamin, Mahmoud Gamal Ameen.

  ObjectiveThis study aimed to identify key prognostic factors for recurrence and disease-free survival in high-risk basal cell carcinoma (BCC) patients, focusing on tumor budding, tumor-infiltrating lymphocytes, and adjuvant radiotherapy.MethodsIn this 5-year retrospective cohort study, 34 patients with high-risk nodular BCC who underwent complete surgical excision were evaluated. Clinicopathological data, including tumor budding and tumor-infiltrating lymphocytes scores, were analyzed. Patients were categorized by recurrence status, and factors influencing recurrence and disease-free survival were assessed using odds ratios with 95% confidence intervals.ResultsThe median age was 63 years (range: 48-82), with 77% men. Tumor budding was detected in 16 patients and was significantly associated with recurrence (odds ratio 3.6, 95% confidence intervals: 1.2-6.8). Low tumor-infiltrating lymphocytes scores (score 1) were also linked to recurrence (odds ratio 4.5, 95% confidence intervals: 1.6-8.2). Patients who did not receive adjuvant radiotherapy had a higher risk of recurrence (odds ratio 5.2, 95% confidence intervals: 2.0-9.1). The 5-year disease-free survival was 47% overall, 80.0% in patients who received radiotherapy, and 0.0% in those who did not.ConclusionTumor budding and low tumor-infiltrating lymphocytes scores are strong predictors of recurrence and poor disease-free survival in high-risk basal cell carcinoma. Adjuvant radiotherapy significantly improves outcomes in advanced-stage patients. These markers may support individualized treatment planning and the use of adjuvant radiotherapy in high-risk settings.

Keywords:  basal cell carcinoma; disease-free survival; radiotherapy; tumor budding; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1177/10668969261419047
JTO Clin Res Rep. 2026 Mar;7(3): 100926

Potential Immune Microenvironment Biomarkers in SCLC: J-TAIL-2 Observational Study.

Masayuki Shirasawa, Makoto Nishio, Kadoaki Ohashi, Atsushi Osoegawa, Eiki Kikuchi, Hideharu Kimura, Yasushi Goto, Junichi Shimizu, Eisaku Miyauchi, Hiroshige Yoshioka, Ichiro Yoshino, Toshihiro Misumi, Yasushi Yatabe, Tatsuya Yoshida, Jumpei Kashima, Masahide Oki, Hisao Ashimura, Yuki Kobayashi, Misa Tanaka, Akihiko Gemma.

   Introduction: Effective predictors of response to atezolizumab plus carboplatin/etoposide (CE) therapy in extensive-stage SCLC (ES-SCLC) remain limited. This exploratory analysis from J-TAIL-2 aimed to identify markers of survival benefit with atezolizumab plus CE therapy in ES-SCLC.
Methods: J-TAIL-2 (ClinicalTrials.gov ID, NCT04501497) was a multicenter observational study that enrolled patients receiving atezolizumab plus CE (ES-SCLC cohort) in clinical practice in Japan per local label and treatment guidelines. In this exploratory analysis, the association of CD8+ tumor-infiltrating lymphocyte (TIL) density and SCLC subtypes (SCLC-A [ASCL1 dominant], SCLC-N [NEUROD1 dominant], SCLC-P [ASCL1/NEUROD1 double-negative with POU2F3 expression], and SCLC-O [ASCL1/NEUROD1 double-negative not otherwise specified]) with overall survival (OS) and progression-free survival (PFS) was evaluated. SCLC subtyping was performed by immunohistochemistry.
Results: SCLC samples (n = 100; data cutoff, February 3, 2023) were categorized as SCLC-A (73%), SCLC-N (16%), SCLC-P (8%), and SCLC-O (3%). Among 96 patients who received first-line atezolizumab plus CE, median age was 72 (range, 39-87) years and 81% were male. Furthermore, 56 patients were classified into the CD8+ TIL-high subgroup and 40 into the TIL-low subgroup. Median (m)PFS with atezolizumab plus CE was 6.1 months (95% confidence interval [CI]: 4.5-7.5) in the TIL-high versus 4.4 months (95% CI: 4.0-5.1) in the TIL-low subgroup (p = 0.01); mOS was 18.4 (95% CI: 11.8-not estimable) versus 10.8 months (95% CI: 7.7-16.2; p = 0.04). mOS and mPFS were not significantly different between SCLC subtypes but were numerically shorter in the SCLC-N group.
Conclusions: CD8+ TIL density is a potential biomarker of clinical benefit in ES-SCLC and may facilitate patient selection for atezolizumab combination therapy.

Keywords:  Atezolizumab; Chemotherapy; Immune microenvironment; Lung cancer; Small cell

DOI:  https://doi.org/10.1016/j.jtocrr.2025.100926
Adv Sci (Weinh). 2026 Mar 07. e22864

Nanomedicine Meets Immunotherapy: Advancing Adoptive Cell Therapy with Nanoparticles in the Treatment of Cancer with Sustainability Perspectives.

Erica Frostegård, Tatiana Bobrova, Amalie Leinebø, Thibault Leray, Shayamita Ghosh, Lorena García-Hevia, Chiara Puccinelli, Lorenzo Riccio, Jacopo Sorani, Davide Bonifazi, Julien Caumartin, Emmanuel Donnadieu, Florence Gazeau, Roland Hischier, Else Marit Inderberg, Mónica L Fanarraga, Maria Loustau, Bernd Nowack, Sébastien Wälchli, Cécilia Ménard-Moyon.

  Immunotherapy has achieved remarkable clinical success in certain cancers, particularly through adoptive cell therapy (ACT), where T cell engineering with chimeric antigen receptor (CAR) has driven major clinical breakthroughs in the treatment of hematologic malignancies. However, efficacy against solid tumors remains limited due to multiple barriers, including the scarcity of tumor-specific antigens, antigen heterogeneity, immunosuppressive tumor microenvironment, and physical obstruction of T cell infiltration by dense extracellular matrix. Nanoparticle (NP)-based approaches can overcome these obstacles and enhance ACT by improving tumor immunogenicity and vascular permeability, while reducing off-target toxicity to healthy tissues. This review discusses different strategies leveraging NPs to enhance ACT, including the delivery of immunomodulators and chemotherapeutics, NP-mediated hyperthermia, magnetic guidance to improve T cell accumulation in tumors, and in vivo NP-mediated generation and activation of CAR T cells. While prioritizing patient safety is essential, it does not fully reflect the range of risks and challenges associated with novel nanomedicines. In this regard, we discuss how integrating environmental impact assessments early in the development process is crucial for identifying key impact areas of concern and steering innovation towards more sustainable and responsible designs. Finally, we also identify current challenges, and discuss potential solutions and future research directions, including safety and sustainability.

Keywords:  chimeric antigen receptor; drug delivery; immunomodulator; magnetic hyperthermia; photothermal therapy

DOI:  https://doi.org/10.1002/advs.202522864
Circulation. 2026 Mar 02.

P16+ Cells Drive Adverse Postischemic Cardiac Remodeling Through CCL8-Mediated Recruitment of Cytotoxic Lymphocytes.

Lei Yan, Jialei Zheng, Zhengkai Lu, Anqi Zhu, Min Ye, Jufeng Meng, Juan Tang, Hui Zhang.

   BACKGROUND: Ischemic heart disease remains a leading cause of mortality worldwide, with adverse remodeling after myocardial infarction driven by inflammation and cardiomyocyte loss. Although cytotoxic lymphocytes exacerbate myocardial injury and P16 marks cellular senescence in diseased hearts, the cell type-specific functions of P16+ populations remain unclear.
METHODS: Using p16-CreER;R26-tdT reporter mice, we mapped P16+ cell heterogeneity after myocardial infarction. Senolytic effects were assessed with combined dasatinib and quercetin treatment. Transcriptomic profiling (bulk and single-cell RNA sequencing) of sorted P16+ cells identified secreted factors, validated through in silico predictions and quantitative polymerase chain reaction. Intercellular communication was analyzed using CellChat. Functional relevance was tested through CCL8 (cytokine [C-C motif] ligand 8) neutralization, Ccl8 deletion in P16+ cells, lymphocyte depletion, and intersectional genetic ablation of P16+ fibroblasts or macrophages using dual-recombinase systems (p16-DreER;Pdgfra-CreER;R26-lr-tdT-DTR and p16-DreER;Cx3cr1-CreER;R26-lr-tdT-DTR).
RESULTS: P16 was induced in fibroblasts, macrophages, coronary endothelial cells, and cardiomyocytes after myocardial infarction. Dasatinib and quercetin treatment selectively eliminated P16+ macrophages and fibroblasts, improving cardiac function. Transcriptomic analysis identified P16+ fibroblasts and macrophages as the main sources of CCL8. CCL8 blockade reduced infiltration of cytotoxic lymphocytes (CD8+ T cells and natural killer cells), decreased cardiomyocyte apoptosis, and enhanced repair. Genetic deletion of Ccl8 in P16+ cells reproduced these benefits. It is important to note that ablation of P16+ fibroblasts, but not macrophages, diminished fibrosis and improved function, and depletion of CD8+ T cell attenuated adverse remodeling.
CONCLUSIONS: P16+ cells orchestrate maladaptive remodeling after myocardial infarction through CCL8-dependent recruitment of cytotoxic lymphocytes, particularly CD8+ T cells, which drive cardiomyocyte apoptosis. Targeting P16+ fibroblasts or blocking CCL8 offers a promising therapeutic approach for ischemic heart disease.

Keywords:  CCL8; P16; cytotoxic lymphocytes; myocardial infarction

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.077172
Cell Signal. 2026 Mar 03. pii: S0898-6568(26)00108-7. [Epub ahead of print] 112458

CLDN18.2 in lung adenocarcinoma as a promising target of chimeric antigen receptor T cells.

Feng Xu, Haidi Xu, Yongkuan Gu, Ran Zhang, Hui Chen.

   OBJECTIVE: An autologous chimeric antigen receptor T (CAR-T) cell therapeutic modality, specifically directed toward Claudin 18.2 (CLDN18.2), was successfully established for lung adenocarcinoma (LUAD).
METHODS: Employing a multimodal integrative approach that combines bulk RNA sequencing datasets, and immunomodulatory factors in LUAD were identified. To verify the function of CLDN18.2 in regulating T cell infiltration, the CLDN18.2 gene was knocked out in the A549 cell culture model with CRISPR-Cas9, and a set of CLDN18.2-/- clones was thereby established. Functional evaluations of CAR-T lymphocytes targeting CLDN18.2 were performed both ex vivo and in vivo. Ultimately, our team aimed to examine whether the antineoplastic efficacy of CLDN18.2-directed CAR-T cells could be further potentiated by combination with a concomitant anti-PD-1 antibody.
RESULT: CLDN18.2 was designated as a putative critical target molecule regulating immune responses in LUAD. Validation experiments utilizing cellular and tissue specimens confirmed that CLDN18.2 expression was elevated in LUAD-derived cells and tissues. Moreover, in vitro CLDN18.2 knockdown suppressed the oncogenic biological abilities of LUAD cells. In vivo studies demonstrated that CLDN18.2-CAR-T therapy induced a gradual and substantial reduction in tumor growth burden. CLDN18.2-CAR-T cells converted immune-cold immunosuppressive tumors into immune-hot immune-activating tumors, and when co-administered with anti-PD1 agents, this therapeutic strategy significantly enhanced the antitumor response.
CONCLUSION: Our findings demonstrated that CLDN18.2-directed CAR-T cells exhibit potential as a potent therapeutic strategy for management of LUAD expressing CLDN18.2.

Keywords:  Anti-PD1 immunotherapy; CLDN18.2; Chimeric antigen receptor T; Lung adenocarcinoma

DOI:  https://doi.org/10.1016/j.cellsig.2026.112458
Br J Cancer. 2026 Mar 06.

Investigating PAK inhibition in combination with PD-1 blockade to enhance cytotoxic CD8+ T cell-mediated killing and suppress invasion of ovarian cancer cells.

Alexandria R Mitchell, Yiran Chen, Giuseppe Pugliese, Gabriela Vino Flores, David M Davies, John Maher, Claire M Wells.

BACKGROUND: P-21 activated kinase (PAK) overexpression, phosphorylation, and gene amplification have been reported to increase cellular invasion in ovarian cancer (ovcan), worsening patient prognoses. One notable method of ovcan survival is through the PD-(L)1 checkpoint pathway, and PD-L1 expression in ovcan is correlated with poor patient outcomes. However, PD-1 and PD-L1 targeted clinical trials in ovcan have shown modest results. This work has examined the possibility of using PAKi and PD-1 blockade as a combination therapy.
METHODS: PAK and PD-L1 expression in ovarian cells was determined. A novel 3D spheroid assay was used to assess ovcan invasion. Ovcan cell viability, downstream pathway signalling, and surface PD-L1 expression were evaluated after treatment with PAK inhibitors and co-culture with cytotoxic CD8+ T cells. Ovcan cell and CD8+ T cell co-cultures were treated with a combination of PAK inhibition and PD-1 checkpoint blockade and ovcan cell viability was assessed.
RESULTS: Ovcan cells showed significant sensitivity to PAKi. CD8+ T cell killing of ovcan cells improved following pre-treatment with PAK inhibitors, and this was further augmented with PD-1 blockade.
DISCUSSION: The work presented here demonstrates the efficacy of PAK inhibition and PD-1 checkpoint blockade as a combination therapy for high-grade serous ovarian cancer.

DOI: https://doi.org/10.1038/s41416-026-03342-z
Pathobiology. 2026 Feb 28. 1-20

CAR-NKT cell therapy for tumors: promise and progress.

Ruo-Bing Wang, Xuan Wang, Kun-Kun Han, Guo-Dong Chen, Yi-Li Yang, Xin Xu, Tao Zhang.

Therapy based on chimeric antigen receptor-engineered invariant natural killer T (iNKT) cells (CAR-NKT cells) is an innovative cellular immunotherapy strategy that offers advantages over conventional CAR-T cell therapy in the treatment of solid tumors. This article reviews the research progress and current application of CAR-NKT cells in solid tumors. Current studies have shown that CAR-NKT cells can efficiently recognize tumor-associated antigens, infiltrate the tumor microenvironment, and exert anti-tumor effects through direct killing and cytokine secretion. Compared with CAR-T therapy, CAR-NKT therapy exhibits stronger anti-tumor potency and a reduced incidence of graft-versus-host disease. Furthermore, CAR-NKT cells can enhance anti-tumor immunity by regulating dendritic cells, NK cells, and CD8⁺ T cells. Early clinical trials for neuroblastoma and preclinical trials for other solid tumors have shown good safety and preliminary efficacy, and therapies have great potential for clinical translation. However, this therapy still faces challenges such as optimizing antigen selection, insufficient in vivo expansion and persistence, tumor heterogeneity, and immune suppression barriers. Future directions include advancing cytokine engineering and combination therapies. Collectively, CAR-NKT cells provide new ideas and new means to break through the difficulties in treating solid tumors and hold the promise of becoming the next generation of cellular immunotherapy.

DOI: https://doi.org/10.1159/000551197