bims-tuinly 2026-05-24 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–05–24
28 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Phenotypic and Functional Characteristics of CD8+ T cells Predict Clinical Outcome Following TIL Therapy in a Randomized Phase III Trial in Advanced Melanoma.
Correction: An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.
Lymph node ratio, not nodal stage, predicts overall and disease-free survival in non-ampullary primary small intestine adenocarcinoma.
Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions.
Spatial Clustering of Recently Activated Cytotoxic Lymphocytes Improves Association with Overall Survival in Women with High-Grade Serous Ovarian Cancer.
The proteomics and phosphoproteomics landscape of melanoma under T cell attack.
Dynamic inflammatory biomarkers as prognostic indicators in advanced breast cancer patients receiving PD-1 inhibitors.
Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear Cell Renal Cell Carcinoma: analyses of the HCRN GU16-260 trial.
Cellular Therapies in Solid Tumors: Are We Ready for Primetime?
Elucidating Tumorigenesis Mechanisms and Assessing Immunotherapeutic Efficacy in Patient-Derived Medulloblastoma Organoid Models.
Association of HAMP Expression and CD8+ T-Cell Infiltration With Atezolizumab-Bevacizumab Response in Hepatocellular Carcinoma.
β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses.
Overcoming Primary and Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer: Mechanisms, Challenges, and Emerging Strategies.
Excalipoint's trispecific T cell engagers for solid tumors.
ASCL2-mediated macrophage-myofibroblast transition generates immunosuppressive CAF_7 in NSCLC bone metastases.
An autologous cell-based therapeutic vaccine expressing IL6/1 fusokine drives robust anti-tumor response against ovarian cancer.
OX40+ regulatory T cells suppress neoadjuvant chemotherapy response in NSCLC and reversed by combination of PD-1 blockade therapy.
Single-cell RNA sequencing unveils CD8+ T cell heterogeneity in the diffuse large B-cell lymphoma microenvironment: A systematic review.
T Cell Dysfunction in the Acidic Tumor Microenvironment.
Progress in Adoptive Cell Therapy for Advanced Gastric Cancer.
TGF-β inhibition enhances anti-tumor immunity and sensitizes PD-1 blockade therapy of bone marrow-derived myofibroblasts-induced "immunotherapy resistance" tumor model.
Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance.
Iron overload in the tumor microenvironment induces CD8+ T cell ferroptosis and dysfunction.
Clinical outcomes and predictors of response to PD-(L)1 blockade in patients with NSCLC without actionable genomic alterations who never used tobacco.
Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer.
Quantitative coupling of clonal CNV evolution and spatially restricted malignant states identifies MFGE8 as a candidate late-state-associated target in breast cancer.
Should checkpoint inhibitors be reserved for biomarker-selected pediatric brain tumors?
Bi-functional anti-LAG-3-IL-2c enhances immune checkpoint inhibitor and CAR T-cell therapy for cancer.

Clin Cancer Res. 2026 May 18.

Phenotypic and Functional Characteristics of CD8+ T cells Predict Clinical Outcome Following TIL Therapy in a Randomized Phase III Trial in Advanced Melanoma.

Joachim S Granhøj, Sigrid M H Mannering, Kasper Madsen, Helle W Hendel, Arianna Draghi, Inge Jedema, Justin Lievense, Cynthia Nijenhuis, Bastiaan Nuijen, Maaike V Zon, Maartje W Rohaan, Willemijn S Tak, Sebastian Klobuch, Troels H Borch, Özcan Met, John Haanen, Marco Donia, Inge Marie Svane.

PURPOSE: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is a highly personalized cancer immunotherapy. In the randomized Phase III clinical trial (TIL-NKI/CCIT), TIL therapy significantly improved progression-free survival (PFS) compared with ipilimumab in patients with unresectable stage IIIC and IV cutaneous melanoma. This study aimed to define phenotypic and functional characteristics of the infused TIL associated with the best overall response (BOR) and PFS.
EXPERIMENTAL DESIGN: Using flow cytometry, we profiled infusion products from all 80 patients treated with TIL in the TIL-NKI/CCIT trial and correlated the results with BOR and PFS. We established autologous tumor cell lines from 24 patients and assessed the anti-tumor reactivity of the infused CD4+ and CD8+ T cells through co-culture assays and intracellular cytokine staining. We quantified tumor-reactive TIL relative to baseline tumor volume and monitored their persistence in the peripheral blood for up to 24 months after infusion.
RESULTS: Responding patients received a higher absolute number of CD8+TCRαβ+ T cells than non-responders (p=0.0290). The frequency of infusion product CD8+TCRαβ+ T cells was strongly associated with PFS at six months (p<0.0001). The number of tumor-reactive CD8+ T cells infused, normalized to baseline tumor burden, correlated with BOR (p=0.0352) and PFS at six months (p=0.0007), with sustained peripheral blood persistence of tumor-reactive CD4+ and CD8+ T cells predictive of durable clinical response.
CONCLUSION: CD8+ T cell phenotype, tumor reactivity, and in vivo persistence emerged as strong predictors of clinical outcome. Our data identify CD8+ T cells as a key determinant of therapeutic efficacy.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4097
Front Bioinform. 2026 ;6 1841924

Correction: An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.

Xia Li, Kang-Lai Wei, Zhao-Quan Huang, Zi-Yan Huang.

  [This corrects the article DOI: 10.3389/fbinf.2026.1764743.].

Keywords:  automated annotation; deep learning; lung adenocarcinoma; pathology; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fbinf.2026.1841924
Hum Pathol. 2026 May 16. pii: S0046-8177(26)00128-0. [Epub ahead of print]175 106159

Lymph node ratio, not nodal stage, predicts overall and disease-free survival in non-ampullary primary small intestine adenocarcinoma.

Eric C Honaker, Omer Saeed, Iván A González.

  Lymph node ratio (LNR) has emerged as a strong prognostic indicator in colorectal cancer (CRC), but its significance in non-ampullary primary small intestine adenocarcinoma (SIA) has been only sparsely reported in the literature. Moreover, LNR has not been examined alongside key CRC histologic prognostic variables, including tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs). Eighty-nine cases (mean age: 63 years, range: 20-88) of SIA were included from 2008 to 2023; most tumors arose in the duodenum (40%). Mean follow-up was 40.9 months (range: 0-189). The mean carcinoembryonic antigen (CEA) level was 38.4 ng/mL (range: 0.2-1183.9). Low-grade histology predominated (69%), and lymphovascular invasion was seen in 42% and perineural invasion in 16%. TB was low in 55%, intermediate in 30%, and high in 15%. DR was mature in 45%, intermediate in 43%, and immature in 12%. TILs were present in 34%. The average International TILs Working Group score was 29% (range: 0-80%). The mean LNR was 0.2, and 49% of cases were pN0. Most tumors were pT3 (54%) or pT4 (34%), and 12% were pM1. Only CEA level and LNR independently predicted disease-free survival (HR: 1.01; 95%CI 1.00-1.02; P = 0.010 and HR 14.64; 95%CI 1.82-117.59; P = 0.012, respectively), and LNR independently predicted overall survival (HR 14.55; 95%CI 1.76-120.06; P = 0.013). Higher LNR was significantly associated with adverse tumor characteristics, including features of the tumor microenvironment such as TB, DR, and TILs. LNR and pre-operative CEA level outperformed nodal stage and other histologic factors as prognostic markers in SIA.

Keywords:  Desmoplastic reaction; Lymph node ratio; Pathology; Small intestine adenocarcinoma; Tumor budding; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.humpath.2026.106159
Acta Pharmacol Sin. 2026 May 18.

Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions.

Ji-Zhao Cao, Wei Zhao, Xiao-Jun Xia.

  Cell-based immunotherapies have emerged as a transformative modality in modern cancer treatment, complementing conventional approaches such as surgery, chemotherapy, radiotherapy, and molecularly targeted therapies. This review provides an integrated and up-to-date synthesis of the rapidly evolving landscape of cellular immunotherapy, encompassing chimeric antigen receptor (CAR) T cells, T cell receptor (TCR)-engineered T cells, tumor-infiltrating lymphocytes (TILs), dendritic cell (DC) vaccines, natural killer (NK) cell-based therapies, and macrophage-directed strategies. We delineate the mechanistic foundations underlying each modality, summarize clinical outcomes across both hematologic malignancies and solid tumors, and critically evaluate therapeutic performance in the context of treatment-associated toxicities, resistance mechanisms, and barriers to durable response. Furthermore, we highlight emerging next-generation strategies designed to mitigate antigen escape, overcome immunosuppressive tumor microenvironments, and address challenges related to manufacturing, scalability, and accessibility. Collectively, these advances establish cell-based immunotherapies as a central component of precision oncology, with expanding potential to deliver durable and broadly accessible clinical benefit across diverse cancer types.

Keywords:  TCR-engineered T cells (TCR-T); chimeric antigen receptor (CAR) T-cell therapy; dendritic cell (DC) vaccines; macrophage-based immunotherapy; natural killer (NK) cell therapy; tumor-infiltrating lymphocyte (TIL) therapy

DOI:  https://doi.org/10.1038/s41401-026-01811-y
Cancer Epidemiol Biomarkers Prev. 2026 May 20. OF1-OF10

Spatial Clustering of Recently Activated Cytotoxic Lymphocytes Improves Association with Overall Survival in Women with High-Grade Serous Ovarian Cancer.

Alex C Soupir, Mary K Townsend, Cassandra A Hathaway, Jonathan Nguyen, Carlos Moran Segura, Daryoush Saeed-Vafa, Oscar E Ospina, Lauren C Peres, Jose R Conejo-Garcia, Kathryn L Terry, Shelley S Tworoger, Brooke L Fridley.

BACKGROUND: A previous study found that adding the spatial context of tumor-infiltrating lymphocytes (TIL) and cytotoxic T lymphocytes (CTL) to abundance improved associations with overall survival (OS) of non-Hispanic Black women with high-grade serous ovarian cancer (HGSOC). This study set out to replicate previous findings in predominantly non-Hispanic White women HGSOC cohorts.
METHODS: Multiplex immunofluorescence was used to characterize TILs in HGSOC from women enrolled in three epidemiologic studies (N = 433). Spatial clustering of TILs was derived using a permutation approach for Ripley K. Cox proportional hazards models were used for associations of spatial clustering and abundance with OS.
RESULTS: In models assessing differences in spatial clustering within tumors with a high abundance of TILs (>1%), we found that spatial information significantly improved the model fit for the recently activated CTLs (likelihood ratio test P = 0.008), in which low spatial clustering in high abundance was associated with a decreased risk of mortality (hazard ratio = 0.31; 95% confidence interval, 0.14-0.70; P = 0.004) compared with when the recently activated CTLs were highly clustered.
CONCLUSIONS: In this study, we replicated the significantly improved association with OS in mostly White women with HGSOC by including spatial information for the recently activated CTLs. Further research is needed to understand the mechanisms by which recently activated spatial architecture affects survival from HGSOC.
IMPACT: This study validates our previous findings that adding spatial context to abundance, especially CTLs or the recently activated CTLs, when performing survival analyses improves the fit of the models.

DOI: https://doi.org/10.1158/1055-9965.EPI-25-1867
Cell Rep Med. 2026 May 21. pii: S2666-3791(26)00246-6. [Epub ahead of print] 102829

The proteomics and phosphoproteomics landscape of melanoma under T cell attack.

Giulia Franciosa, Agnete W P Jensen, Ana Martinez-Val, Ilaria Piga, Marco Donia, Jesper V Olsen.

  Understanding how tumor cells interact with tumor-infiltrating lymphocytes (TILs) is crucial for improving immunotherapy, yet protein-level changes remain largely unexplored. To address this, we profile the early responses of patient-derived melanoma cells co-cultured with matched autologous TILs. To distinguish tumor from TIL proteomes without physical sorting, we apply stable isotope labeling by amino acids in cell culture (SILAC) coupled with Orbitrap Astral data-independent acquisition (DIA) mass spectrometry (MS). This approach enables cell type-specific profiling of protein phosphorylation and degradation, alongside bulk analysis of the early newly synthesized proteome during active immune attack. Our analyses resolve interferon-γ-dependent changes in melanoma cells, identify the cytotoxic and regulatory T cell molecule (CRTAM) as a selective marker of reactive TILs, and reveal rapid tumor-intrinsic activation of DNA damage response-associated kinases, exposing potential therapeutic vulnerabilities. Overall, this framework provides a powerful resource for dissecting tumor-immune interactions to guide biomarker discovery and advance immunotherapy.

Keywords:  CRTAM; DNA-PK; TILs; cancer; cell signaling; immunotherapy; mass spectrometry; melanoma; phosphoproteomics; proteomics

DOI:  https://doi.org/10.1016/j.xcrm.2026.102829
Ther Adv Med Oncol. 2026 ;18 17588359261443939

Dynamic inflammatory biomarkers as prognostic indicators in advanced breast cancer patients receiving PD-1 inhibitors.

Na Wang, Peijun Yi, Qianyi Lu, Yi Zhong, Cong Xue, Ping Zhang, Shusen Wang, Zhongyu Yuan, Yanxia Shi, Hanmu Chen, Fei Xu, Kuikui Jiang.

   Background: While programmed cell death protein 1 (PD-1) inhibitors benefit breast cancer patients, simple predictors of their efficacy are lacking.
Objectives: This study aimed to evaluate inflammatory markers as prognostic indicators for advanced breast cancer (ABC) patients receiving immunotherapy.
Design: This is a single-center retrospective study of ABC patients treated with PD-1 inhibitors between January 2016 and June 2022.
Methods: Clinicopathological parameters, tumor-infiltrating lymphocytes (TILs) levels, and inflammatory markers-C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR)-were collected from 116 ABC patients at baseline and after three cycles of immunotherapy (CRP3, NLR3, LMR3). Optimal cut-offs were defined using R software and associations with progression-free survival (PFS), overall survival (OS), and objective response rate were assessed.
Results: Low baseline CRP, low NLR, and high LMR were significantly associated with improved PFS and OS (all p < 0.05) by Kaplan-Meier analysis. On multivariate analysis, low NLR3 and a reduced CRP3/CRP ratio independently predicted prolonged PFS (p < 0.05). Patients with low CRP, reduced CRP3/CRP ratio, low NLR, and low NLR3 achieved better OS (p < 0.05). Combining inflammatory markers with TIL status improved prognostic classification: TIL-deficient patients with high NLR3 (median PFS (mPFS): 2.89 months) or high CRP3/CRP ratio (mPFS: 1.90 months) had the poorest survival (p < 0.05).
Conclusion: CRP and NLR are promising biomarkers for predicting outcomes of PD-1 inhibitor therapy in ABC, with potential utility in individualizing immunotherapy strategies.

Keywords:  C-reactive protein; advanced breast cancer; immunotherapy; neutrophil-to-lymphocyte ratio; prognostic biomarker; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1177/17588359261443939
Clin Cancer Res. 2026 May 18.

Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear Cell Renal Cell Carcinoma: analyses of the HCRN GU16-260 trial.

Nourhan El Ahmar, Morgan A Paul, Berkay Simsek, Sayed Matar, Opeyemi A Jegede, Yasmin Nabil Laimon, Varunika Savla, Razan Mohanna, Gabriel Roberti de Oliveira, Aseman Bagheri Sheshdeh, Thomas Denize, Destiny J West, Maxwell D Seager, Maxine Sun, Toni K Choueiri, Wanling Xie, Gordon J Freeman, Arlene H Sharpe, David A Braun, Naomi B Haas, Hans Hammers, Mehmet A Bilen, Mark Stein, Jeffrey A Sosman, Catherine J Wu, David F McDermott, Michael B Atkins, Sabina Signoretti.

PURPOSE: We investigated components of the immune tumor microenvironment as determinants of clinical outcome to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with frontline nivolumab in the phase 2, non-randomized HCRN GU16-260 trial.
EXPERIMENTAL DESIGN: Pre-treatment primary ccRCCs from 72 patients were analyzed by multiplex immunofluorescence and image analysis to assess non-terminally exhausted CD8+ (CD8⁺PD-1⁺TIM3⁻LAG3⁻) tumor-infiltrating lymphocytes (TILs), PD-1+ regulatory T cells (Tregs), total and peritumoral tertiary lymphoid structures (TLS), and CD163+ tumor-associated macrophages (TAMs). Clinical endpoints included objective response rate (ORR) and progression-free survival (PFS).
RESULTS: Densities of CD8⁺PD-1⁺TIM3⁻LAG3⁻ TILs, total and peritumoral TLS, and CD163⁺ TAMs, as continuous variables, were associated with improved ORR (Odds Ratio: 1.54 [1.10-2.16] for TILs; 1.18 [1.02-1.37] for total TLS; 1.10 [1.02-1.18] for peritumoral TLS; 2.21 [1.33-3.69] for TAMs) and longer PFS (Hazard Ratio: 0.79 [0.67-0.95] for TILs; 0.92 [0.85-0.99] for total TLS; 0.94 [0.90-0.98] for peritumoral TLS; 0.77 [0.61-0.97] for TAMs). Although % of PD-1+ Tregs as continuous variable was not associated with outcomes, at an optimal cut-off, high % of PD-1+ Tregs tended to be associated with lower ORR (12.5% vs 43.6%, p=0.093) and was associated with shorter PFS (3.4 vs 10.9 months, p<0.001). The biomarkers were not strongly correlated with each other and their integration in multi-biomarker models further stratified outcomes.
CONCLUSION: Individual immune cell populations within the ccRCC microenvironment are associated with response/resistance to frontline anti-PD-1 therapy. Our findings support the development of combined immune marker models to identify patients with divergent outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-26-0216
JCO Oncol Pract. 2026 May 20. OP2600119

Cellular Therapies in Solid Tumors: Are We Ready for Primetime?

Giuseppe Maiocco, Vinicius Ernani, Michael P Gustafson, Salman R Punekar, Konstantinos Leventakos, Julian Molina, Yousef Zakharia, Mitesh Borad, Antonious Z Hazim.

Adoptive cellular immunotherapy (ACT) has revolutionized hematologic malignancies, yet translation to solid tumors has historically been limited. This landscape shifted significantly in 2024 with US Food and Drug Administration approvals of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel, an engineered T-cell receptor (TCR) therapy for synovial sarcoma. These approvals mark the clinical arrival of ACT for solid tumors and highlight a rapidly expanding therapeutic landscape. Beyond these indications, multiple ACT platforms including TIL, TCR, chimeric antigen receptor (CAR) T-cell, CAR-natural killer, and CAR-macrophage therapies are under active clinical investigation across diverse solid tumor indications. Clinical experience to date has defined key barriers to efficacy, including impaired tumor trafficking, antigen heterogeneity, immunosuppressive tumor microenvironment, and limited cellular persistence. In parallel, rapid advances in cellular engineering are reshaping the field, with the development of armored constructs, logic-gated and multiantigen targeting strategies, innate immune-based platforms, and novel manufacturing approaches including allogeneic and in vivo cell engineering. As ACT enters clinical practice for select solid tumors, distinct toxicity profiles and logistical requirements necessitate careful patient selection and multidisciplinary coordination. Early biomarker testing, timely referral to specialized centers, and familiarity with evolving toxicity management frameworks are increasingly critical. Here, we seek to provide a practice-oriented framework for understanding emerging ACT platforms, clinical data, toxicity considerations, and implementation strategies relevant to contemporary solid tumor oncology care.

DOI: https://doi.org/10.1200/OP-26-00119
Int J Biol Sci. 2026 ;22(9): 4878-4899

Elucidating Tumorigenesis Mechanisms and Assessing Immunotherapeutic Efficacy in Patient-Derived Medulloblastoma Organoid Models.

Jiting Zhang, Min Wang, Huanwen Rui, Cen Wang, Guanghao Luo, Zhiyuan Niu, Wei Shi, Junwei Zeng, Ping Xue, Xueyao Shi, Bing Yan, Wenyan Ren, Hao Li, Xinhua Lin.

  Medulloblastoma is one of the most common malignant pediatric brain tumors. There remain significant challenges in investigating oncogenic mechanisms and evaluating therapeutic efficacy due to the limited available models that accurately reflect tumor heterogeneity. To overcome this limitation, we established 10 patient-derived medulloblastoma organoids (MBOs) that retain the histological characteristics, and cellular diversity of the original tumors. These MBOs demonstrate strong infiltration capabilities, both in vitro through co-culture with human embryonic stem cell-derived cerebral organoids and in vivo following orthotopic or subcutaneous transplantation, establishing a potential platform for investigating interactions within the tumor microenvironment. Using integrated RNA sequencing, whole-exome sequencing, and DNA methylation profiling, we demonstrated that MBOs faithfully preserve the transcriptional, genomic, and epigenetic landscapes of their parental tumors. Single-cell transcriptomic analysis revealed conserved cellular subpopulation between MBOs and primary tumors. Our findings suggest that photoreceptor-related pathways may play an unprecedented role in the pathogenesis of Group 4 medulloblastoma and may be associated with interactions within the tumor microenvironment. Furthermore, we developed a prognostic nomogram based on IMPG2, BNC2, PAPPA2, ITGBL1and UNC13C expression levels in tumor cells to predict survival outcomes. Notably, tumor-infiltrating lymphocytes (TILs) expanded from patient specimens exhibited significant cytotoxic activity against autologous MBOs co-cultured in vitro and effectively suppressed the growth of subcutaneous MBO xenografts in vivo. These findings demonstrate the potential of TIL-based immunotherapy for medulloblastoma treatment. Collectively, our MBO system faithfully recapitulates critical tumor characteristics and serves as a valuable platform for investigating tumorigenic mechanisms and assessing therapeutic responses. This study not only promotes fundamental biological research but also accelerates clinical translation in medulloblastoma.

Keywords:  immunotherapy; medulloblastoma; organoids; single-cell sequencing; tumorigenesis

DOI:  https://doi.org/10.7150/ijbs.116040
Ann Gastroenterol Surg. 2026 May;10(3): 871-882

Association of HAMP Expression and CD8+ T-Cell Infiltration With Atezolizumab-Bevacizumab Response in Hepatocellular Carcinoma.

Shun Nakamura, Yuki Murakami, Yusuke Oshima, Takashi Masuda, Wataru Miyoshino, Hiroomi Takayama, Yoko Kawano, Teijiro Hirashita, Yuichi Endo, Masafumi Inomata.

   Aim: Atezolizumab combined with bevacizumab is the standard first-line therapy for unresectable hepatocellular carcinoma; however, predictive biomarkers of therapeutic response remain undefined. We aimed to identify molecular features associated with therapeutic efficacy to develop personalized treatment strategies.
Methods: Transcriptomic analyses were performed using public RNA-sequencing datasets of patients with hepatocellular carcinoma receiving anti-PD-L1-based therapy, comparing responders (complete response/partial response) with non-responders (stable disease/progressive disease). Differentially expressed genes and enriched pathways were identified using integrated differential expression and pathway analysis. For validation, RNA-sequencing was performed on institutional tumor samples (n = 6) underwent. Immunohistochemistry was performed on resected specimens (n = 9) to evaluate CD8+ tumor-infiltrating lymphocytes and hepcidin protein expression encoded by the HAMP gene. Group comparisons for the pre-specified immunohistochemistry endpoints were analyzed using exact Wilcoxon rank-sum tests with multiplicity control (Holm adjustment).
Results: Analysis of public datasets revealed distinct expression profiles in responders, enriched in immune-related and chemokine signaling pathways. Candidate genes, including HAMP, TAT, and HRG, were upregulated in responders. In institutional samples, HAMP expression was significantly higher in preoperatively treated tumors (p = 0.001). Immunohistochemistry demonstrated greater CD8+ tumor-infiltrating lymphocyte density (median 36.6 vs. 5.0 cells/high-power field; exact Wilcoxon p = 0.032) and higher HAMP immunoreactive scores (median 4 vs. 0.5; p = 0.032) in responders than in non-responders.
Conclusions: Upregulation of HAMP and hepcidin protein expression, together with increased CD8+ T-cell infiltration, was associated with a favorable response to atezolizumab-bevacizumab in patients with hepatocellular carcinoma. HAMP may serve as a component of a composite biomarker predictive of therapeutic sensitivity, warranting validation in larger, multi-institutional cohorts.

Keywords:  RNA‐sequencing; atezolizumab; bevacizumab; hepatocellular carcinoma; hepcidin

DOI:  https://doi.org/10.1002/ags3.70158
Cancer Immunol Immunother. 2026 May 20.

β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses.

Yupan Bai, Han Xue, Yujie Bao, Yue Pan, Jiayin Tang, Mengna Wang, Ying Wang, Jie Xu, Jing Huang.

  Ketogenic diets (KDs) have been reported to influence tumor progression through metabolic and immunological modulation of the tumor microenvironment. β-hydroxybutyrate (βOHB), the predominant ketone body elevated by KD, functions not only as an energy substrate but also as a potent signaling metabolite. Despite its role in modulating the tumor microenvironment, the direct impact of βOHB on the function of CD8+ T cell, a key mediator of anti-tumor immunity, remains incompletely understood. Here, we demonstrate that βOHB suppresses tumor growth in multiple mouse tumor models by enhancing the accumulation, survival, and effector function of tumor-infiltrating CD8+ T cells. In contrast, acetoacetate does not exert comparable immunomodulatory effects. Mechanistically, βOHB upregulates the Tcf7-Lck signaling pathway by engaging with the cell surface receptor Hcar2, an effect potentially working in parallel with its role as an HDAC inhibitor. Knockdown of either Tcf7 or Hcar2 in CD8+ T cells abolishes the promoting effect of βOHB on CD8+ T function. Our findings elucidate a metabolite-immune axis that directly regulates the functional state of tumor-infiltrating CD8⁺ T cells and provide experimental evidence linking ketone metabolism to anti-tumor immune regulation.

Keywords:  Anti-tumor therapy; CD8+ T cell; Lck; Tcf7; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s00262-026-04420-0
J Clin Oncol. 2026 May 22. JCO2503026

Overcoming Primary and Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer: Mechanisms, Challenges, and Emerging Strategies.

Cassio Murilo Hidalgo-Filho, Valentina Santo, Eleonora Gariazzo, Mihaela Aldea, Federica Pecci, François-Xavier Danlos, Gilberto de Castro Junior, Biagio Ricciuti.

Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable clinical benefit in non-small cell lung cancer (NSCLC). Emerging after initial responses, AR reflects tumor evolution, immune escape, and metabolic reprogramming. Key mechanisms may include impaired antigen presentation (β2-microglobulin, human leukocyte antigen mutations), T-cell exhaustion, and remodeling of the tumor microenvironment (TME). In this review, we summarize the current understanding of ICIs resistance and highlight therapeutic strategies under investigation to overcome it. Novel approaches include next-generation ICIs targeting TIGIT and LAG-3, epigenetic modulators (HDAC, DNMT inhibitors), and metabolic agents relevant to STK11 and KEAP1 mutations. Additional strategies aim to reprogram the TME through AXL or multikinase inhibition, tumor-treating fields, and cytokine- and/or gene-based therapies. Cellular immunotherapies (tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptor-T), antibody-drug conjugates, and vaccines offer complementary means to restore antitumor immunity. Advancing the field will require biomarker-driven patient selection and rational combinations to overcome AR and achieve more durable, personalized immunotherapy outcomes in NSCLC.

DOI: https://doi.org/10.1200/JCO-25-03026
Nat Biotechnol. 2026 May;44(5): 677

Excalipoint's trispecific T cell engagers for solid tumors.

DOI: https://doi.org/10.1038/s41587-026-03151-y
J Exp Clin Cancer Res. 2026 May 18.

ASCL2-mediated macrophage-myofibroblast transition generates immunosuppressive CAF_7 in NSCLC bone metastases.

Jinfeng Wang, Jin Qian, Xiujia Yang, Chongquan Huang, Tiantian Wei, Jielong Zhou, Guoqing Zhong, Zhenhai Zhang, Yu Zhang.

   BACKGROUND: NSCLC frequently metastasizes to bone, where the microenvironment becomes immunosuppressive, limiting immunotherapy efficacy. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) contribute to immune evasion, but CAF subset origins and roles in bone metastases remain unclear. We investigated whether TAMs undergo macrophage-to-myofibroblast transition (MMT) to generate an immunosuppressive CAF subpopulation in bone lesions, driven by ASCL2.
METHODS: We integrated single-cell RNA sequencing of primary lung tumors and bone metastases with pseudotime and regulon analyses to resolve CAF heterogeneity and nominate MMT regulators. Findings were validated by immunofluorescence and flow cytometry in patient tissues and a murine bone-metastasis model. In vitro, TGF-β1-induced MMT with ASCL2 knockdown/rescue and T-cell co-culture assays were used to assess CAF_7-like induction and immunosuppressive function. In vivo, macrophage depletion/reconstitution, donor and endogenous tracing, and macrophage-directed ASCL2 or Il6ra knockdown were performed in a mouse bone-metastasis model to assess CAF_7-like abundance, tumor burden, and T-cell states; ASCL2 inhibition was further evaluated with PD-1 blockade for tumor control and survival.
RESULTS: Seven CAF subsets were identified, including a bone metastasis-enriched subset (CAF_7) that co-expressed macrophage, MHC-II, and stromal markers. Trajectory analyses, together with the observation that LLC-conditioned medium induced a CAF_7-like shift in bone marrow-derived macrophages in vitro and that both exogenous GFP-labeled BMDMs and endogenous macrophage-lineage-traced cells acquired CAF_7-like features in the bone metastatic microenvironment, supported TAM-to-CAF_7-like transition via MMT. CAF_7 accumulation correlated with increased Treg infiltration, CD8⁺ T cell exhaustion, and poorer survival. Regulon analysis highlighted ASCL2 as a CAF_7-associated regulator; ASCL2 increased in vitro during MMT, and in vivo ASCL2 protein and ASCL2⁺ CAF_7-like cells were enriched in bone-metastasis lesions versus sham marrow or subcutaneous tumors. ASCL2 knockdown in macrophages blocked MMT, reducing CAF_7-like cells and associated Treg and exhausted CD8⁺ T cells, and suppressing tumor growth. Mechanistically, ASCL2 directly transactivated Il6ra, and macrophage Il6ra knockdown phenocopied ASCL2 silencing in vivo. Notably, ASCL2 silencing synergized with anti-PD-1 therapy, improving tumor control and extending survival.
CONCLUSIONS: In NSCLC bone metastases, ASCL2-driven MMT converts TAMs into immunosuppressive CAF_7 that promotes immune escape. Targeting ASCL2 disrupts this transition, restores anti-tumor immunity, and may improve immunotherapy efficacy.

Keywords:  ASCL2; Bone metastases; Cancer-associated fibroblasts (CAF); Il6ra/IL6R; Immunosuppression; Macrophage-myofibroblast transition (MMT); Non-small cell lung cancer (NSCLC); Tumor‐associated macrophages (TAM)

DOI:  https://doi.org/10.1186/s13046-026-03735-1
bioRxiv. 2026 May 08. pii: 2026.05.05.721149. [Epub ahead of print]

An autologous cell-based therapeutic vaccine expressing IL6/1 fusokine drives robust anti-tumor response against ovarian cancer.

Sejal Sharma, Rahul Das, Andrea Pennati, Catigan Hedican, Lisa Barroilhet, Manish S Patankar, Jacques Galipeau.

Background: Cytokines are immunomodulatory proteins that play central roles in regulating immune responses and represent attractive targets for cancer therapy. However, as single agents, cytokines have shown limited clinical benefit due to systemic toxicities and a short in vivo half-life. Our group has focused on engineering fusion cytokines (fusokines) that couple two cytokines into a single biologic to reprogram immune cell responses by enforcing non-canonical receptor engagement and signaling. A chimeric IL-6/IL-1β fusokine was engineered to test the hypothesis that enforced co-engagement of IL-6 and IL-1β signaling pathways would confer a gain-of-function phenotype in T cells and promote robust anti-tumor immunity. Here, we describe the immunomodulatory properties of IL6/1 fusokine and a method to deliver this fusokine to produce inhibition of ovarian tumor growth in a pre-clinical mouse model.
Methods: Lentiviral vectors encoding murine or human IL6/1 were designed using Vector Builder and expressed in either HEK293, CHO or ID8-F3 (p53 -/- ) cells depending on the downstream experiment to be conducted. IL6/1 expression was validated by ELISA and flow cytometry. Effects of human IL6/1 (hIL6/1) on T cell function (proliferation, memory phenotype, activation induced apoptosis) were monitored by flow cytometry. For in vivo studies, ID8-F3 murine ovarian cancer cells expressing mouse IL6/1 (mIL6/1) were administered intraperitoneally (I.P.) as a cell-based therapy to C57BL/6 female mice bearing established ID8-F3 luciferase tumors. Tumor progression was monitored by bioluminescence (BLI) imaging, and overall survival was evaluated.
Results: hIL6/1 significantly enhanced T cell survival and selectively promoted activation and expansion of CD45RO⁺ memory T cells. mIL6/1 expressing ID8-F3 cells (ID8IL6/1) demonstrated stable transduction and sustained cytokine secretion. In vivo, ID8IL6/1 cell therapy significantly reduced tumor growth and improved overall survival compared to control groups, with 2 of 8 mice achieving complete tumor clearance.
Conclusion: These findings indicate that IL6/1 fusokine enhances T cell survival and proliferation while promoting memory responses. Engineered cancer cells (ID8-F3) expressing mIL6/1 fusokine induced a strong anti-tumor response when delivered as a therapeutic vaccine in ovarian cancer mouse model.
What is already known on this topic: Fusokines are a class of bifunctional proteins designed to achieve synergistic immune modulation. Previous studies in our lab have shown fusokine exhibit gain-of-function immunomodulating activity. Individually, IL-6 and IL-1β are recognized for their roles in promoting T-cell proliferation and effector function. However, the potential for a fused IL-6/1 fusokine to reprogram the immune system and elicit a superior anti-tumor response in vivo in ovarian cancer model is not yet studied.
What this study adds: This study develops a novel fusion cytokine (fusokine), combining IL-6 and IL-1β, and demonstrate robust activation of T cells. In a preclinical ovarian cancer model, engineered cancer cells expressing IL6/1 used as a therapeutic vaccine showed significant tumor reduction and improved overall survival.
How this study might affect research practice or policy: This study demonstrates that in comparison to individual cytokines, fusokines have greater potential to activate T cell function and when delivered as a cell therapy, achieve clear therapeutic efficacy in an ovarian cancer model. Further translational and clinical studies may enable the development of novel and more effective fusokine cell therapy approaches for patients with ovarian cancer.

DOI: https://doi.org/10.64898/2026.05.05.721149
Lung Cancer. 2026 May 15. pii: S0169-5002(26)00519-2. [Epub ahead of print]217 109458

OX40+ regulatory T cells suppress neoadjuvant chemotherapy response in NSCLC and reversed by combination of PD-1 blockade therapy.

Jiali Zhang, Rui Liu, Qingqing Hui, Yulong Chen, Jing Luo, Yang Wang, Zhaoxiang Ye, Xiubao Ren, Zhenzhen Hui.

   BACKGROUND: OX40+ regulatory T cells mediate tumor immune escape and correlate with clinical response to neoadjuvant therapy in NSCLC, but the underlying mechanisms remain incompletely understood.
METHODS: We collected formalin-fixed paraffin-embedded (FFPE) tumor sections from 30 NSCLC patients receiving neoadjuvant chemotherapy (NAC) and 28 patients receiving neoadjuvant PD-1 blockade and chemotherapy (NAPC), and explored the effect of OX40+ Tregs on the efficacy of neoadjuvant therapy and the level of immune cell infiltration by multiplex immunofluorescence staining (mIHC).
RESULTS: Our results showed that the proportion of OX40+ Tregs was significantly increased after NAC. NAPC led to elevated infiltration of Th17 cells and Tregs within tumors, while OX40+ Tregs were markedly reduced. In patients achieving major pathological response (MPR) following NAPC, total Treg levels remained unchanged, but OX40+ Tregs decreased significantly and showed a strong negative correlation with tumor necrosis rate. Spatial analysis revealed that after NAPC, Tregs and OX40+ Tregs tended to decrease in proximity to CD8+ T cells, whereas Th17 cells increased significantly. Tumor cells were surrounded by higher densities of CD4+ T cells, Th17 cells, and CD8+ T cells. Furthermore, patients with MPR after NAPC exhibited fewer Tregs and OX40+ Tregs adjacent to CD8+ T cells and more CD8+ T cells encircling tumor cells.
CONCLUSIONS: Our study reveals the critical role of Treg/Th17 balance in tumor immunotherapy and demonstrates that OX40+ Tregs inhibit the neoadjuvant chemotherapy response in NSCLC, which can be reversed by combining with PD-1 blockade via boosting Th17 cells, providing new insights to improve the efficiency of chemoimmunotherapy for NSCLC.

Keywords:  CD8(+) T cells; NSCLC; OX40(+) Tregs; PD-1 blockade; Th17; Treg/Th17 balance; mIHC

DOI:  https://doi.org/10.1016/j.lungcan.2026.109458
Crit Rev Oncol Hematol. 2026 May 16. pii: S1040-8428(26)00268-4. [Epub ahead of print]224 105381

Single-cell RNA sequencing unveils CD8+ T cell heterogeneity in the diffuse large B-cell lymphoma microenvironment: A systematic review.

Alimire Maimaiti, Xiaolong Qi, Zhenghao Zhang, Yan Li.

   BACKGROUND: The heterogeneous response to immunotherapy in diffuse large B-cell lymphoma (DLBCL) is largely attributable to the diverse functional states of CD8⁺ T cells within the tumor microenvironment. Although single-cell RNA sequencing (scRNA-seq) has revolutionized cellular resolution, a systematic synthesis of this evidence to map CD8⁺ T cell heterogeneity and its clinical implications in DLBCL is currently lacking.
METHODS: Following the PRISMA guidelines and a PROSPERO-registered protocol (CRD420261282336), we conducted a qualitative systematic review (without meta-analysis) of 18 eligible scRNA-seq studies published up to September 2025. Dual reviewers independently performed study selection, data extraction, and quality assessment using a self-designed scRNA-seq checklist combined with the AMSTAR-2 tool.
RESULTS: We constructed a dynamic exhaustion trajectory atlas of CD8⁺ T cells in DLBCL, revealing a hierarchical continuum comprising multiple functionally distinct subclusters. Key findings include: ① the progenitor exhausted T cell (Tpex) subset is associated with favorable prognosis and holds therapeutic targetability, whereas the terminally exhausted (Tex-term) subset correlates with poor prognosis; ② the CXCR5⁺TCF7⁺ S1 subset predicts sensitivity to RB-CHOP chemotherapy, and CD58 pathway impairment is linked to CAR-T resistance; and ③ the recently identified CD8‑fit cells show promise as a synergistic immunotherapy target.
CONCLUSION: This review provides a comprehensive single-cell atlas of CD8⁺ T cells in DLBCL, advocating a shift toward cell‑state‑guided precision immunotherapy. The identified biomarkers facilitate pre‑treatment patient stratification and reveal novel combinatorial targets. Future multicenter studies should focus on validating these targets (e.g., CD58, CD8‑fit) and standardizing scRNA‑seq analytical frameworks to translate these findings into clinical practice.

Keywords:  CD8-positive T-lymphocytes; Diffuse large B-cell lymphoma; Single-cell RNA sequencing; Systematic review; T-cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105381
Acta Physiol (Oxf). 2026 Jun;242(6): e70260

T Cell Dysfunction in the Acidic Tumor Microenvironment.

F B Christiansen, E S Novella, A V Lindemann, J F H Cordes, S F Pedersen.

  Solid tumors are characterized by profound metabolic and vascular abnormalities that generate a hostile tumor microenvironment (TME) marked by extracellular acidosis, hypoxia, and nutrient deprivation. While the consequences of these conditions for cancer cell behavior have been extensively studied, their impact on anti-tumor immune responses-particularly T cell function-has only recently gained attention. In this review, we summarize and critically discuss current knowledge on how acidic TME conditions affect the cytotoxic CD8+ T cells which are essential for anti-tumor immunity, and the protumorigenic, regulatory T cells (Tregs). An emerging body of literature shows that TME acidosis restricts cytotoxic CD8+ T cell motility and tumor penetration, suppresses cytokine production and secretion despite preserved transcription, impairs proliferation, and reduces cytotoxic killing capacity. These effects are closely linked to acid-induced metabolic reprogramming, including inhibition of glycolysis, altered mTOR and MYC signaling, and a shift toward fatty acid-dependent oxidative metabolism. In contrast, Tregs, which are metabolically adapted to rely on oxidative phosphorylation and lactate utilization, are comparatively resilient to acidic stress, and acidosis can enhance their suppressive capacity, thereby further skewing the immune balance toward tolerance. We highlight emerging evidence that tumor acidosis modulates immune checkpoint pathways, including pH-sensitive signaling through VISTA and regulation of PD-L1 expression, with important implications for immunotherapy sensitivity. We posit that limiting tumor acidosis may enable restoration of anti-tumor T cell function and improve therapeutic response to immune checkpoint blockade and adoptive T cell therapies.

Keywords:  CD8+; Treg; anticancer immune response; cancer; immune oncology

DOI:  https://doi.org/10.1111/apha.70260
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2026 May 19.

Progress in Adoptive Cell Therapy for Advanced Gastric Cancer.

Jia-Rang Liu, Shao-Qiu Dai, Ming-Yu Duan, Chen Huang, Zai Luo.

  Although great progress has been achieved in radiotherapy,chemotherapy,and molecular targeted therapy for gastric cancer in recent years,the clinical benefits for patients with gastric cancer are very limited due to the high heterogeneity of gastric cancer.As the research on the immune microenvironment and the progression mechanism of solid cancers keeps advancing,accumulating evidence indicates that adoptive cell transfer therapy (ACT),as a novel precision therapy,holds important potential clinical applications in solid tumors such as gastric cancer.Chimeric antigen receptor T cell (CAR-T) therapy,T cell receptor-engineered T cell (TCR-T) therapy,natural killer (NK) cell therapy,etc.can inhibit the proliferation and metastasis of gastric cancer cells by conjugating specific antigen recognition components with T cells,genetically engineering T cells,and expanding and reinfusing NK cells in vitro.They exhibit particularly favorable therapeutic effects in patients with unresectable and metastatic gastric cancer.This article reviews the therapeutic principles,classification,main targets,and current treatment status of ACT and explores the opportunities and challenges it faces in the precision treatment of advanced gastric cancer,aiming to provide new ideas for the clinical treatment of gastric cancer.

Keywords:  adoptive cell transfer therapy; immunotherapy; stomach neoplasms

DOI:  https://doi.org/10.3881/j.issn.1000-503X.16660
Cancer Immunol Immunother. 2026 May 22.

TGF-β inhibition enhances anti-tumor immunity and sensitizes PD-1 blockade therapy of bone marrow-derived myofibroblasts-induced "immunotherapy resistance" tumor model.

Xin Cheng, Lina He, Cong Zhou, Qingli Li, Baiwen Zhang, Jianzheng Wang, Xiaojiao Cheng, Shuiping Tu.

  Resistance to immune checkpoint blockade (ICB) therapy in certain solid tumors remains a major research focus; yet, the underlying mechanisms are not fully understood. Our previous studies demonstrated that subcutaneous tumors formed by a mixture of bone marrow-derived myofibroblasts (BMFs) and tumor cells not only grew faster than those formed by tumor cells alone but were also resistant to ICB therapy. However, the specific mechanism by which BMFs mediate this immune resistance remained unclear. In this study, we established a "BMF + MC38" mixed-cell subcutaneous tumor model to further validate its ICB therapy-resistant phenotype, investigate the mechanism underlying BMF-mediated immune resistance, and explore potential therapeutic strategies for this "immune-excluded" type of tumor. Our findings revealed that "BMF + MC38" mixed-cell subcutaneous tumors lost sensitivity to anti-PD-1 antibody treatment. Furthermore, these mixed-cell subcutaneous tumors exhibited significantly impaired CD8+ T cell infiltration and function, along with an increased proportion of regulatory T cells (Tregs). Higher expression of TGFβ1 was detected in the mixed-cell tumors compared to the MC38 cell tumors. Importantly, either reducing BMF-derived TGFβ1 expression or concurrently targeting PD-1 and TGFβ effectively restored the sensitivity to PD-1 blockade, rescued CD8+ T cell infiltration and function. Additionally, this study revealed that simultaneously targeting PD-1, TGFβ, and VEGFR further suppressed the growth of these mixed-cell subcutaneous tumors. These findings provide a viable combination targeted therapy strategy for the clinical treatment of solid tumors that are insensitive to immunotherapy.

Keywords:  Bone marrow-derived myofibroblasts; Combination therapy; Immunotherapy resistance; Transforming growth factor-β

DOI:  https://doi.org/10.1007/s00262-026-04428-6
bioRxiv. 2026 May 05. pii: 2026.04.30.721705. [Epub ahead of print]

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance.

Ines Delclaux, Katherine S Ventre, Naomi R Besson, Tara Muijlwijk, Milad Ibrahim, Guanning Wang, Taylor A Heim, Maria M Steele, Alexander C Huang, Markus Schober, Iman Osman, Amanda W Lund.

Successful anti-tumor immune surveillance depends on stem-like CD8 + T cells that are enriched in tumor-draining lymph nodes (LN), but how they are maintained over time remains poorly understood. Here, we identify a continuous lymphatic circuit that sustains stem-like CD8 + T cells. Using photoconversion to fate-map intratumoral T cells we demonstrate that effector cells exit the tumor microenvironment and migrate back to the draining LN. These tumor-specific, migratory effector T cells avoid chronic antigen stimulation, re-express the transcription factor associated with self-renewal, TCF1, and enter a stem-like state in the LN. Antigen presentation in LNs by dendritic cells drives their proliferation thereby inflating the LN stem-like population. Consequently, maintenance of stem-like T cells and ICB response depends on constitutive lymphatic transport, while LN metastasis compromises the stem-like niche, diminishing ICB response. We, therefore, define a continuous, peripheral lymphatic circuit that recycles tumor-experienced effector T cells to fuel durable, systemic immune surveillance.

DOI: https://doi.org/10.64898/2026.04.30.721705
Nat Commun. 2026 May 22.

Iron overload in the tumor microenvironment induces CD8+ T cell ferroptosis and dysfunction.

Zhenyu Lin, Huanpeng Chen, Yujing Ke, Hanyue Xiao, Chao Li, Zilong Wu, Huixin Gao, Nanqi Huang, Lijuan Lu, Peng Sun, Yingjie Bian.

While iron homeostasis in cancer cells is well-established, its role in mediating crosstalk between tumors and CD8+ T cells within the tumor microenvironment (TME) remains largely elusive. In this study, we compare iron levels across primary tissues populated by CD8+ T cells. Contrary to the systemic iron deficiency commonly found in cancer patients, the TME exhibits marked iron enrichment compared to lymphatic fluid and peripheral blood, a phenomenon primarily attributed to tumor necrosis. However, this iron-overloaded TME is detrimental to CD8+ T cells, triggering their ferroptosis and dysfunction. Mechanistically, tumoral T cell receptor (TCR) hyperactivation and tumor-derived hepcidin cooperatively downregulate the iron exporter SLC40A1 in CD8+ T cells, leading to intracellular iron accumulation and ferroptosis. Both genetic restoration of SLC40A1 and iron chelation inhibit CD8+ T cell ferroptosis and restore their cytotoxic activity, thereby suppressing tumor growth. Finally, to enhance chimeric antigen receptor T (CAR-T) cell adaptability to the iron-overloaded TME, we engineer SLC40A1-overexpressing CAR-T cells. These engineered cells resist ferroptosis induced by the TME and elicit potent anti-tumor immunity.

DOI: https://doi.org/10.1038/s41467-026-73379-4
Clin Cancer Res. 2026 May 18.

Clinical outcomes and predictors of response to PD-(L)1 blockade in patients with NSCLC without actionable genomic alterations who never used tobacco.

Eleonora Gariazzo, Arielle Elkrief, Kyle Concannon, Daniele Ognissanti, Alessandra Dodi, Valentina Favorito, Alessandro Di Federico, Andrea De Giglio, Leonardo Brunetti, Valentina Santo, Federica Pecci, Mihaela Aldea, Edoardo Garbo, Joao V Alessi, Jaclyn LoPiccolo, Francesco Paoloni, Mizuki Nishino, Lynette M Sholl, Narjust Florez, Julia Rotow, Stacey M Frumm, Lingzhi Hong, Jianjun Zhang, Don Gibbons, Xinan Wang, Lorenza Landi, Laura Cipriani, Mehrdad Rakaee, Alessio Cortellini, Marcello Tiseo, Federico Cappuzzo, Andrea Ardizzoni, Mark M Awad, John V Heymach, Stefano Scalera, Marcello Maugeri-Saccà, Giulio Metro, Natalie Vokes, Adam Schoenfeld, Biagio Ricciuti.

PURPOSE: Predictive biomarkers of response to immune checkpoint inhibitors (ICI) remain poorly defined in patients with non-small cell lung cancer (NSCLC) without a history of tobacco use and lacking actionable genomic alterations (AGA). We aimed to identify clinical and molecular predictors of response to ICI-based regimens in patients who have never smoked and lack AGA.
EXPERIMENTAL DESIGN: We retrospectively analyzed patients with metastatic, AGA-negative NSCLC who never smoked, treated with ICI-based regimens across multiple independent cohorts. Tumor-infiltrating lymphocyte (TIL) densities were quantified using a machine learning-based algorithm, and immune cells biomarkers were assessed with multiplexed immunofluorescence. Transcriptomic correlates of ICI response were analyzed in the SU2C cohort.
RESULTS: Among 741 patients with AGA-negative NSCLC and no history of tobacco use, objective response rate (ORR) was 23.2%, median progression-free survival (mPFS) 4.5 months, and median overall survival (mOS) 16.8 months. PD-L1≥90% and TMB≥90th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all p<0.01). PD-(L)1+CTLA-4 combinations outperformed chemo-immunotherapy and PD-(L)1 monotherapy in terms of mPFS and mOS. Transcriptomic analysis revealed enrichment of innate and adaptive immune pathways in responders, including increased MHC class I/II antigen presentation and T-cell activity. High TIL density was also associated with superior ORR and PFS. Multiplexed immunophenotyping confirmed higher immune cell infiltration in patients who experienced durable clinical benefit.
CONCLUSIONS: We demonstrated how combination therapies may improve ICI outcomes in patients with AGA-negative NSCLC and no history of tobacco exposure. Very high PD-L1, TMB, and immune-enriched phenotypes may guide treatment personalization.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4793
Nat Immunol. 2026 May 20.

Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer.

Han Dong, Arindam Ray, Lara K Rotter, Jinhua Wang, Isabella Grabski, Heemaja Mewada, Lulu Wang, Kun Huang, Ye Tian, Maxime Meylan, Graham Barlow, Chenyang Yu, Mahesh Raundhal, Sung-Hee Yoon, Shreya Nakhawa, Liya Ding, Jean J Zhao, Ursula A Matulonis, Marc Foretz, Kai W Wucherpfennig, Rafael A Irizarry, Marc N Wein, Laurie H Glimcher.

Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.

DOI: https://doi.org/10.1038/s41590-026-02512-8
J Transl Med. 2026 May 21.

Quantitative coupling of clonal CNV evolution and spatially restricted malignant states identifies MFGE8 as a candidate late-state-associated target in breast cancer.

Zhangwen Ge, Liuxian Wu, Shu Wang, Xukui Li, Tao Wang.

   BACKGROUND: Breast cancer progression reflects heterogeneous malignant states shaped by clonal evolution and microenvironmental selection, yet how genomic instability quantitatively couples to transcriptional state transitions and spatial niche organization remains unclear.
METHODS: We integrated single-cell RNA sequencing and spatial transcriptomics across ER-positive, HER2-positive, and triple-negative tumors, combined with CNV inference, branched trajectory analysis, transcription factor regulon modeling, cell-cell communication inference, and spatial niche mapping. Trajectory-derived evolutionary gene programs were translated to bulk-tumor stratification and multicohort prognostic modeling. MFGE8 was further evaluated as a therapeutic target using structure-based virtual screening with docking and molecular dynamics refinement. Functional validation of MFGE8 was performed using knockdown, overexpression, rescue, and in vitro phenotypic assays.
RESULTS: Malignant epithelial cells formed a branched three-state trajectory that was strongly coupled to CNV-defined clonal architecture, with the tightest coupling in triple-negative tumors. Regulon analyses revealed coordinated transcription factor rewiring along progression, converging on a late State 3 program enriched for extracellular matrix and adhesion signaling. Spatial transcriptomics localized State 3 to a discrete invasive-front niche characterized by stromal-dominant ligand-receptor interactions. MFGE8 emerged as a State 3-biased output associated with LHX2 activity, and in silico MFGE8 perturbation induced transcriptional rollback from the late-state branch. Structure-guided screening prioritized candidate MFGE8 binders with stable interaction dynamics. Evolutionary gene programs enabled robust bulk stratification and supported a multicohort-validated 10-gene prognostic model associated with genomic instability patterns and immunotherapy-related signatures.
CONCLUSIONS: CNV-linked clonal evolution and spatial niche restriction are associated with a late malignant program and prioritize MFGE8 as a candidate late-state-associated therapeutic target in breast cancer.

Keywords:  Breast cancer; CNV inference; Clonal evolution; MFGE8; Spatial transcriptomics

DOI:  https://doi.org/10.1186/s12967-026-08308-6
J Neurooncol. 2026 May 16. pii: 2. [Epub ahead of print]178(1):

Should checkpoint inhibitors be reserved for biomarker-selected pediatric brain tumors?

Yaxel Levin-Carrion, Jayant Bhasin, Kevin Titkov, Sraavya Anne, Arman Sawhney, Caryn J Ha, Ibraheem Sharaf, Marvens Jean, Jacob Santana, Drew Thibault, Alejandro Pando, Nemanja Novakovic, Nehal S Parikh, Morana Vojnic, Jonathan H Sherman.

   PURPOSE: Pediatric brain tumors, including high-grade gliomas (HHG), medulloblastomas (MB), and ependymomas (EPN), are a leading cause of death in children. They are often immunologically "cold" with low tumor mutational burden (TMB) and very few tumor-infiltrating lymphocytes (TILs), which may limit the role of immune checkpoint inhibitors (ICI).
METHODS: We performed a PRISMA‑guided systematic review of PubMed/MEDLINE, Embase, and Scopus from inception to September 17, 2025, for English-language studies of patients ≤ 21 years with primary CNS tumors treated with PD‑1/PD‑L1 or CTLA‑4 inhibitors. Eligible reports included prospective trials, retrospective series, and observational/case reports with extractable data on efficacy and/or toxicity. Of 479 records identified, 386 unique citations were screened, 127 underwent full‑text review, and 40 met inclusion criteria for qualitative synthesis.
RESULTS: Prospective and institutional studies in biomarker-unselected diffuse midline glioma, high-grade glioma, medulloblastoma, and ependymoma showed low objective response rates (generally ≤ 6%), short median progression-free survival (1-3 months), and overall survival similar to historical controls, despite acceptable safety (grade ≥ 3 treatment-related adverse events ~ 15-25% with anti-PD-1 ± anti-CTLA-4). In contrast, across germline MMR-deficient and broader RRD/hypermutant cohorts, PD-1 blockade produced clinically meaningful and sometimes durable responses, including complete remissions in malignant glioma and approximate 2-year overall survival near 50%, often with delayed responses and pseudoprogression. Histology-specific profiling highlighted marked variation in immune contexture: pediatric gliomas segregate into immune "hot," "altered," and "cold" subtypes; medulloblastoma is largely PD-L1-low with prominent B7-H3 and myeloid programs; checkpoint expression is also observed in germ cell and selected sellar tumors. Evidence quality is limited by small, heterogeneous, predominantly non-comparative designs.
CONCLUSION: ICIs show manageable safety but limited efficacy in unselected pediatric CNS tumors. Durable benefit is most evident in RRD/hypermutant biology and possibly PD-L1-high niches (e.g., some low-grade gliomas and CNS-GCT). Future trials should be biomarker-driven and pair ICIs with priming combinations (e.g., radiation, epigenetic modulators, metronomic chemotherapy) to convert "cold" tumors into responders.

Keywords:  CTLA-4; Hypermutation; Immune checkpoint inhibitors; Mismatch repair deficiency; PD-1/PD-L1 blockade; Pediatric CNS tumors; Tumor immune microenvironment

DOI:  https://doi.org/10.1007/s11060-026-05605-4
iScience. 2026 Jun 19. 29(6): 115849

Bi-functional anti-LAG-3-IL-2c enhances immune checkpoint inhibitor and CAR T-cell therapy for cancer.

Fang Huang, Jianing Huang, Fan Ye, Shih Chieh Chen, Wen-Chin Huang, Botong Hua, Ella Yumin Li, Jenny Jiang, Joyce Kwan, Hanna Lin, Wenli Shi, Honglin He, Mingxing Yang, Qiang Fu, Binfeng Lu, Ziyang Zhong.

  The effectiveness of cancer immunotherapies in solid tumors is often limited by challenges such as transient efficacy and low response rates. T-cell exhaustion is one key mechanism that impairs T-cell function in the tumor microenvironment (TME), compounded by the absence of immune-stimulatory signals. In this study, we developed a strategy leveraging an engineered fusion protein, anti-LAG-3-IL-2c, which combines an anti-LAG-3 antibody for targeting tumor-reactive T-cells with an interleukin-2 mutein complex (IL-2c). The fusion protein is designed to boost therapeutic efficacy while minimizing toxicity. Our in vitro and in vivo studies showed that anti-LAG-3-IL-2c selectively targets activated T-cells and CAR T-cells. In addition, combining anti-LAG-3-IL-2c with anti-PD-1 further enhanced antitumor activities. Furthermore, our results demonstrated that anti-LAG-3-IL-2c significantly improved the efficacy of CAR T-cell therapy for solid tumors. Our findings underscore the potential of targeted IL-2 delivery through anti-LAG-3 antibodies as a promising and effective approach to cancer immunotherapy.

Keywords:  cellular therapy; immunology; microenvironment; oncology; precision medicine

DOI:  https://doi.org/10.1016/j.isci.2026.115849