bims-tuinly 2026-03-01 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–03–01
37 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor-infiltrating lymphocytes demonstrate potent anti-tumor efficacy and synergize with PD-1 blockade in bladder cancer.
Tumor-Infiltrating lymphocyte dynamics as biomarkers of neoadjuvant treatment response in luminal breast cancer.
Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function.
Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.
Clinicopathologic, genetic and immune cell infiltration analysis of colorectal signet ring cell carcinoma with comparison to conventional adenocarcinoma.
Impact of immune-related adverse events on response to neoadjuvant chemoimmunotherapy in triple-negative breast cancer: a single-institution retrospective study.
A computer vision method to evaluate tumor-infiltrating lymphocytes and multiparametric modeling of neoadjuvant systemic therapy response in breast cancer.
Enhancing Patient Lymphocyte Response to Peritoneal Malignancies Using a Personalized Immunocompetent Microfluidic Co-Culture Platform.
Spatial immunophenotyping of tumor-associated macrophages predicts prognostic outcomes in clear cell renal cell carcinoma.
Epstein-Barr Virus Infection Is Associated with an Elevated Tumor-Stroma Ratio and Older Age in Oral Squamous Cell Carcinoma.
Ready or Not, Here They Come: A Practical Guide to Adoptive T cell Therapies for Solid Tumors for Medical Oncologists.
Advances in the management of metastatic lobular breast cancer: Current evidence and emerging treatments.
Specific depletion of TIGIThigh CD226- clonally expanded intratumoral Tregs defines safe and effective TIGIT targeting.
CT-Based Radiomics Predicts the Functional State of Tumor-Infiltrating CD8+ T Cells and Prognosis in NSCLC.
Integrated chronic in vivo and in vitro screens uncover NFIL3 as a driver of T cell dysfunction.
Characterization of a hybrid hydrogel for the studying of lymphocyte infiltration and migration in a 3-dimensionalin vitrotumor stroma device.
Piezo1 as a mechanical checkpoint in T cell immunotherapy for solid tumors.
Circulating ex-Trm CD8 + T cells with skin-homing/chemoattraction phenotype are associated with disease severity in atopic dermatitis.
Pretreatment tumor infiltrating lymphocytes and outcome in patients with HR+/HER2- advanced breast cancer treated with CDK4/6 inhibitors.
A Framework for Comparing Mouse Neoantigen Immunogenicity.
Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells.
Integrative analysis of T cell subset-specific ICOS expression and tumor HLA class I/II expression in lung adenocarcinoma: implications for their interaction and clinical outcome.
VSIG4 restricts hepatocellular carcinoma control by suppressing tumor-specific CD8+ T cell immunity in the tumor microenvironment.
The Proximity of PD-1-CD103+ Tissue-Resident CD8+ T Cells to Tumor Cells Is Correlated with Improved Clinical Outcomes in Patients with Cholangiocarcinoma.
Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
Cardiotoxicity of T cell immunotherapies.
Identification of a Highly Functional Effector CD8+ T Cell Program after Transplantation in Mice and Humans.
Diffusion Relaxation-Correlated Spectroscopic MR Imaging for In Vivo Tumor Heterogeneity and Lymph Node Metastasis Prediction in Oral Tongue Squamous Cell Carcinoma.
PD-1 protects expanding human T cells from premature restimulation-induced cell death by modulating TCR and CD28 signaling.
Comparative analysis of clinicopathological characteristics and prognosis between E-cadherin-negative breast lymphoepithelioma-like carcinoma and E-cadherin-negative invasive lobular carcinoma.
DADA Enhances CD8+ T Cell Stemness to Improve Anti-Tumor Immunity and Immunotherapy Efficacy.
Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.
"Armoring" CAR T Cells Bolsters Activity against Solid Tumors.
Discover personalized drug opportunity and optimized tumor-infiltrating lymphocyte therapy for rare cancer: an organoid-based whole-journey clinical mapping study in a neuroendocrine cancer patient.
A woman with hypoxemia and bilateral alveolar opacities following tumor-infiltrating lymphocyte and interleukin-2 infusion.
CD30 Expression in Neoplastic Mast Cells and the Presence of CD30+, CD3+, and PAX-5+ Tumour-Infiltrating Lymphocytes as Prognostic Markers in Canine Cutaneous Mast Cell Tumours.
Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial.

J Transl Med. 2026 Feb 26.

Tumor-infiltrating lymphocytes demonstrate potent anti-tumor efficacy and synergize with PD-1 blockade in bladder cancer.

Guan-Kai Huang, Xin-Xin Zhang, Lin-Yuan Huang, Hio-Cheng Un, Ren-Xuan Lin, Jun-Xing Chen, Zong-Ren Wang, Ling-Li Long.

   BACKGROUND: Bladder cancer (BCa) is one of the most prevalent urological malignancies globally with substantial clinical challenges characterized by high recurrence rates and limited treatment options for advanced disease. Although immune checkpoint inhibitors (ICIs) provide clinical benefit, their efficacy is restricted, with objective response rates of only 20-25%. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown remarkable success in other solid tumors but remains largely unexplored in BCa. The emergence of patient-derived organoids (PDO) offers a physiologically relevant ex vivo platform for functionally evaluating TIL by preserving tumor heterogeneity.
METHODS: TIL were isolated from BCa patient specimens and robustly expanded ex vivo using interleukin-2 (IL-2) and a rapid expansion protocol (REP). Expansion efficiency was quantified, and TIL phenotypes were characterized via flow cytometry. Transcriptional and clonal dynamics were profiled using single-cell RNA sequencing (scRNA-seq) coupled with T-cell receptor (TCR) sequencing. The anti-tumor efficacy of TIL, both as monotherapy and in combination with the PD-1 inhibitor Nivolumab, was assessed against BCa cell lines and autologous PDO through viability (ATP), cytokine release (IFN-γ, ELISA), and apoptosis (caspase 3/7) assays. In vivo validation was performed in a 5637 cell-line-derived xenograft (CDX) mouse model.
RESULTS: TIL were successfully expanded from 33 of 48 BCa samples with high yields of viable cells. Expanded TIL were predominantly CD8 + cytotoxic T lymphocytes. Integrated scRNA and TCR-seq analysis revealed that REP enriched for cytotoxic effector clones and reduced regulatory T-cell populations. TIL mediated potent tumor-killing efficacy against BCa cell lines and autologous PDO in vitro and significantly suppressed tumor growth in vivo. Critically, combining TIL with Nivolumab synergistically enhanced tumor cell death in PDO and resulted in near-complete tumor suppression in the CDX model, significantly outperforming TIL monotherapy.
CONCLUSIONS: TIL isolated from bladder cancer patients can be robustly expanded in vitro into a population enriched with CD8⁺ T cells, which exhibited potent anti-tumor activity across both in vitro and in vivo models. Notably, combining TIL with PD-1 blockade significantly enhanced efficacy, establishing TIL-based adoptive cell therapy as a viable immunotherapeutic strategy for bladder cancer and provide a compelling rationale for the clinical translation of TIL combined with Nivolumab.

Keywords:  Bladder cancer; PD-1 blockade; Patient-derived organoids; Single cell sequencing; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s12967-026-07924-6
BMC Cancer. 2026 Feb 27.

Tumor-Infiltrating lymphocyte dynamics as biomarkers of neoadjuvant treatment response in luminal breast cancer.

Esma Uguztemur, Merve Dogan.



Keywords:  Delta-TIL; HR+/HER2– breast cancer; Neoadjuvant chemotherapy; Pathological complete response (pCR); Tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.1186/s12885-026-15795-9
bioRxiv. 2026 Feb 10. pii: 2026.02.08.704716. [Epub ahead of print]

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function.

Nicole E Scharping, Xuezhen Ge, Maria Inês Matias, Fulin Jiang, Allison Cafferata, Maximilian Heeg, Alexander Monell, Giovanni Galletti, Kitty P Cheung, Angelica Rock, Nick Thao, Sydnye L Shuttleworth, Michael A Bauer, Kennidy K Takehara, Amir Ferry, Sara Quon, Brian Koss, Samuel A Myers, Eric J Bennett, Ananda W Goldrath.

Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation to an 'exhausted' state. In healthy tissues, tissue-resident memory T cells (T RM ) maintain protection for years, and patient tumors that contain TIL with T RM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing T RM and progenitor-exhausted TIL from terminally-exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins in spite of functional proteasome activity. Enforced expression of these ligases by TIL preserved stem-like TCF1 + populations and improved anti-tumor function, whereas their knockout impaired TIL and altered T cell differentiation in acute infection. Sustained ligase expression rescued accumulation of unfolded proteins in TIL and improved immunotherapy outcome in preclinical models, highlighting the critical role of proteostasis in TIL function and identifying new avenues for advancing cancer immunotherapy.

DOI: https://doi.org/10.64898/2026.02.08.704716
Cell. 2026 Feb 24. pii: S0092-8674(26)00102-9. [Epub ahead of print]

Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.

Matthew L Miller, Timothy J Thauland, Smriti Sameer Nagarajan, Wenqi Ellen Zuo, Miguel A Moreno Lastre, Manish J Butte.

  Solid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a β-1,4-glycosidic bond that animals (or their tumors) cannot hydrolyze, but fungi and microbes have evolved enzymes to catabolize cellobiose into useful glucose. We equipped mouse T cells and human chimeric antigen receptor (CAR)-T cells with two proteins derived from fungi that enable import and hydrolysis of cellobiose, and we demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing. Engineered T cells offered cellobiose suppress tumor growth and prolong survival. Offering exclusive access to a natural disaccharide augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.

Keywords:  CAR-T cell; T cells; cellobiose; glucose; immunotherapy; metabolism; tumors

DOI:  https://doi.org/10.1016/j.cell.2026.01.015
J Natl Cancer Cent. 2026 Feb;6(1): 30-39

Clinicopathologic, genetic and immune cell infiltration analysis of colorectal signet ring cell carcinoma with comparison to conventional adenocarcinoma.

Yang An, Jiaolin Zhou, Lan Su, Lin Cong, Xinxin Mao, Bo Chen, Yuhua Gong, Yaping Xu, Han Chen, Chentong Wang, Guole Lin, Huanwen Wu.

   Objective: We sought to characterize the genomic and immune landscape of signet ring cell carcinoma (SRCC), a rare and aggressive subtype of colorectal cancer (CRC).
Methods: Tissue samples and clinicopathological data were retrospectively analyzed from 37 SRCC and 172 conventional adenocarcinomas (AC) of rectum and sigmoid colon. The genetic and immune profiles were assessed using DNA next-generation sequencing (NGS) and multiplex immunohistochemistry.
Results: Compared to AC, SRCC patients were younger, had higher tumor, node, metastasis (TNM) stages and tumor grades (all P < 0.05), and exhibited significantly worse 3-year disease-free survival (DFS) and overall survival (OS) (both P < 0.0001). SRCC exhibited fewer somatic mutations in well-known CRC driver genes including APC (32 % vs. 74 %), KRAS (16 % vs. 42 %), and FBXW7 (0 vs. 20 %), but showed higher frequencies of genetic alterations in SMAD4, RNF43, BCL2L11 (present only in SRCC), MYC, and ARID2 (all P < 0.05). SRCC showed significantly higher levels of CD8+ tumor-infiltrating lymphocytes (TILs), but lower PD-1+CD8+ TILs in both stroma and intratumoral regions (all P < 0.05). Interestingly, high PD-1+CD8+ TILs in intratumoral regions significantly predicted longer DFS and OS in all SRCC and stage II-III SRCC patients (all P < 0.05), while CD3+ or CD8+ TILs did not. Moreover, the characteristic immune cell infiltration correlated with specific genetic alterations in SRCC.
Conclusions: Colorectal SRCC is a clinically and molecularly distinct and highly malignant subtype compared to AC. It exhibits a "pseudo-T cell-inflamed" tumor microenvironment with increased total CD8+ TILs but reduced PD-1+CD8+ TIL infiltration. Notably, PD-1+CD8+ TIL infiltration is associated with favorable prognosis. These findings provide new insights into tumor-immune interactions in SRCC, with potential implications for prognostic stratification and the development of personalized immunotherapeutic strategies.

Keywords:  Genetic alterations; Prognosis; Programmed cell death protein 1; Signet ring cell carcinoma; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jncc.2025.06.006
Breast Cancer Res Treat. 2026 Feb 23. pii: 18. [Epub ahead of print]216(2):

Impact of immune-related adverse events on response to neoadjuvant chemoimmunotherapy in triple-negative breast cancer: a single-institution retrospective study.

Michelle Sterpi, Nechama Dreyfus, Yungtai Lo, Susan Fineberg, Harjot Gill, Della Makower.

   PURPOSE: Immune-related adverse events (irAEs) have emerged as a potential surrogate marker for immunotherapy response across tumor types. We evaluated the association between irAEs and pathologic complete response (pCR) in a racially diverse cohort of patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemoimmunotherapy.
METHODS: We conducted a retrospective analysis of 46 patients with early-stage TNBC treated with neoadjuvant chemoimmunotherapy between January 2021 and March 2023 at a single NCI-designated Comprehensive Cancer Center. irAEs, tumor-infiltrating lymphocytes (TILs), and clinicopathologic characteristics were abstracted from the medical record. Associations with pCR were analyzed using Fisher's exact and Wilcoxon rank-sum tests.
RESULTS: Among 46 patients, the median age was 60.5 years. Most identified as Black (n = 27, 58.7%) or Hispanic (n = 14, 30.4%). irAEs occurred in 13 patients (28.2%), most commonly hypothyroidism, rash, and arthritis. The pCR rate was 55.8% (24/43 evaluable patients). Patients who developed irAEs were more likely to achieve pCR (84.6% vs. 45.2%, p = 0.039). Higher TILs (median 29%) were associated with pCR both as a continuous variable (p = 0.004) and categorically (p = 0.002), but not with irAE development (p = 0.341). pCR was more common among Hispanic patients (p = 0.005), and inversely associated with Black race (p = 0.003) and older age (p = 0.028).
CONCLUSION: IrAEs may serve as a surrogate for treatment response to neoadjuvant chemoimmunotherapy in early TNBC. Additionally, racial and age-based differences in treatment response suggest underlying immunologic or biologic variation. These findings highlight the importance of diverse cohort representation in immunotherapy studies and warrant validation in prospective trials.

Keywords:  Immune-related adverse events; Neoadjuvant chemotherapy; Pembrolizumab; Triple-negative breast cancer; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s10549-026-07930-8
Ther Adv Med Oncol. 2026 ;18 17588359261417762

A computer vision method to evaluate tumor-infiltrating lymphocytes and multiparametric modeling of neoadjuvant systemic therapy response in breast cancer.

Mateusz Bielecki, Fang-I Lu, Angeline Vo, Eileen Rakovitch, Katarzyna J Jerzak, Roberto Salgado, Raffi Karshafian, William T Tran.

   Background: Neoadjuvant systemic therapy (NST) is often used to treat locally advanced breast cancer (BC) or patients with early-stage BC at high risk for micrometastatic spread. Pathological complete response (pCR) to NST in BC is associated with excellent prognostic outcomes; however, rates vary significantly. Tumor-infiltrating lymphocytes (TILs) are associated with NST response, suggesting potential as predictive biomarkers.
Objective: To develop a computer vision approach to quantify spatial TIL parameters and a multiparametric machine learning (ML) model for predicting NST response.
Design: Retrospective, single institution study of 411 BC patients, combining clinical and graph-level pre-treatment histopathology data to predict response to NST using ML.
Methods: Pre-treatment core needle biopsies were prepared, stained with hematoxylin and eosin, and digitized into whole slide images. Convolutional neural networks were applied to segment and classify regions of invasive carcinoma and TILs. Spatial features were extracted based on the coordinates of the TILs within invasive regions, including metrics from Delaunay triangulation, Voronoi diagram analysis, and minimum spanning trees, as well as features capturing cell density and nuclear count. Clinicopathological features were incorporated to support multiparametric modeling. Multiple ML classification models were trained to predict pCR. Logistic regression, K-nearest neighbor, support vector, random forest, Gaussian Naïve Bayes, and extreme gradient boosting models were tested, and model performances were reported.
Results: ML models using clinical and graph-based features achieved high predictive accuracy. The best performing graph feature model reached an area under the receiver operating characteristic curve (AUC) of 0.924. Ensemble models integrating clinical and graph features showed the highest performance, with an AUC of 0.955. Notably, for triple-negative BC, significant differences in predictive performance were demonstrated between clinical and graph feature models (p = 0.026) and between clinical and ensemble models (p = 0.006).
Conclusion: Multiparametric modeling utilizing clinicopathological and graph features obtained from TILs is associated with pCR in BC patients treated with NST.

Keywords:  advanced breast cancer; machine learning; neoadjuvant systemic therapy; prediction models; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1177/17588359261417762
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706377. [Epub ahead of print]

Enhancing Patient Lymphocyte Response to Peritoneal Malignancies Using a Personalized Immunocompetent Microfluidic Co-Culture Platform.

Cecilia R Schaaf, Damian C Hutchins, Tiefu Liu, Mitra Kooshki, Calvin J Wagner, Nicholas Edenhoffer, Nadeem Wajih, Steven D Forsythe, Robyn Geissinger, Edward A Levine, Perry Shen, Pierre Triozzi, Lance D Miller, Adam R Hall, Shay Soker, Konstantinos I Votanopoulos.

Harnessing patient immune cells via adoptive cellular therapy is a promising cancer therapeutic strategy. However, major challenges remain for advanced solid malignancies, including difficulty isolating sufficient tumor infiltrating lymphocytes (TILs) and limited targeting of diverse neoantigens in heterogenous tumors. To address this, we have developed a tumor-on-a-chip platform with co-cultured patient-derived tumor cells, autologous peripheral blood mononuclear cells (PBMCs), and lymphoid tissue-derived antigen presenting cells. This approach generates organoid interacting lymphocytes (OILs) with enhanced anti-tumor activity. In peritoneal malignancies, OIL-induced cytotoxicity of patient-matched tumor cells surpasses both TILs and static-expanded PBMCs. We find that this improved performance was linked to increased CD8 + T and NK cells among OILs, and increased effector cytokine polyfunctionality, particularly Granzyme A. Our platform represents a versatile and scalable approach to generate patient-specific therapeutic lymphocytes even when TILs are insufficient, offering a promising avenue to treat diverse solid tumors associated with poor outcomes under current immunotherapies.
Teaser: A tumor-on-a-chip device primes patient immune cells with tumor recognition for personalized immunotherapy applications.

DOI: https://doi.org/10.64898/2026.02.19.706377
Urol Oncol. 2026 Feb 26. pii: S1078-1439(26)00049-9. [Epub ahead of print]44(5): 111038

Spatial immunophenotyping of tumor-associated macrophages predicts prognostic outcomes in clear cell renal cell carcinoma.

Jisu Uh, Jisup Kim, Su-Jin Shin, Jiwon Ko, Heounjeong Go.

   INTRODUCTION: Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, has high rates of metastasis and recurrence. Its tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs), influences immune evasion and tumor progression. This study evaluated the prognostic significance of TAM and TIL subsets based on their phenotypes and spatial distribution within the TME.
MATERIALS AND METHODS: This retrospective study included 643 ccRCC patients who underwent surgery at Asan Medical Center between 2011 and 2013. Multiplex immunofluorescence staining was performed on tissue microarrays from central and peripheral tumor regions. Markers for M1/M2 macrophages and T cells were quantified using automated imaging software, and optimal cutoffs were defined using maximally selected rank statistics, with additional sensitivity analyses performed to assess robustness. Survival outcomes were assessed with Cox regression, and group comparisons used appropriate statistical tests.
RESULTS: High central density of M2-like TAMs (CD68+CD206+) was associated with poor overall, metastasis-free, and progression-free survival (PFS) (P < 0.05). In contrast, high central density of M1-like TAMs (CD68+iNOS+) was associated with favorable PFS (P = 0.034). M2-like TAMs were more abundant than M1-like across all tumor regions. Peripheral CD3+ TILs were more frequent than in the center. Exploratory analyses showed weak correlations between immune cell densities and response to tyrosine kinase inhibitor therapy.
CONCLUSION: Distinct phenotypes and spatial distributions of TAMs were associated with prognostic outcomes in ccRCC. Central M2-like TAMs were associated with poor outcomes, while central M1-like TAMs were linked to favorable prognosis. TILs did not demonstrate independent prognostic value.

Keywords:  Clear cell renal cell carcinoma; Multiplex immunofluorescence; Tumor microenvironment; Tumor-associated macrophages; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.urolonc.2026.111038
Viruses. 2026 Feb 14. pii: 241. [Epub ahead of print]18(2):

Epstein-Barr Virus Infection Is Associated with an Elevated Tumor-Stroma Ratio and Older Age in Oral Squamous Cell Carcinoma.

Eris Nurul Rahmadhini, Irna Sufiawati, Hasrayati Agustina, Okky Husain, Seto Adiantoro Sadputranto, Adi Idris.

  Epstein-Barr virus (EBV) is an oncogenic virus implicated in several epithelial malignancies; however, its role in the tumor microenvironment of oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the association between EBV infection and clinicopathological and microenvironmental features of OSCC. A cross-sectional analysis was conducted on 62 archived OSCC biopsy specimens. EBV was detected using polymerase chain reaction (PCR), and clinical data were obtained from medical records. Tumor-stroma ratio (TSR), perineural invasion (PNI), lymphovascular invasion (LVI), and histological differentiation were assessed microscopically, while tumor-infiltrating lymphocytes (TILs) were quantified using ImageJ software version 1.54j (National Institutes of Health, Bethesda, MD, USA). EBV DNA was identified in 43.5% of cases. EBV positivity was significantly associated with older age (p = 0.046), especially among patients aged 60 years or older. All EBV-positive tumors exhibited a high tumor-stroma ratio, which was significantly associated with EBV status (p = 0.031). No significant associations were observed between EBV status and sex, tumor site, clinical stage, TILs, PNI, LVI, or histological differentiation. These findings indicate that EBV-positive OSCC is characterized by distinct microenvironmental features, particularly an elevated tumor-stroma ratio, and suggest a potential role for EBV status in microenvironmental profiling and prognostic stratification.

Keywords:  Epstein–Barr virus; clinicopathological features; oral squamous cell carcinoma; tumor microenvironment; tumor stroma ratio; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/v18020241
Oncologist. 2026 Feb 25. pii: oyaf431. [Epub ahead of print]

Ready or Not, Here They Come: A Practical Guide to Adoptive T cell Therapies for Solid Tumors for Medical Oncologists.

Tuan Hoang, Sameena Khan, Adrian Sacher.

  Adoptive cell therapies (ACTs) include chimeric antigen receptors (CARs), bispecific T cell engagers (BiTES), tumor infiltrating lymphocytes (TILs) and T cell receptor (TCR) gene modified T cells. ACTs have significantly improved patient outcomes associated with hematologic malignancies. Recent advances have demonstrated their potential in solid tumors with promising clinical trial results signaling that they represent paradigm shift in oncologic care. As these therapies become standard care in solid tumors, medical oncologists must become adept at recognizing and managing their unique toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This review synthesizes the latest clinical data on ACTs in solid tumors, highlighting key findings and toxicity profiles. In addition, the review provides an overview of early recognition and evidence-based management of CRS and ICANS. Equipping clinicians with the necessary knowledge to navigate toxicity management will be essential in optimizing patient outcomes as ACTs are increasingly adopted in solid tumor oncology.

Keywords:  Adoptive cell therapy; Bispecific T cell engager (BiTE); CAR-T cell; Immune effector cell-associated neurotoxicity syndrome (ICANS); cytokine release syndrome (CRS); solid tumors

DOI:  https://doi.org/10.1093/oncolo/oyaf431
Semin Oncol. 2026 Jan 16. pii: S0093-7754(26)00010-2. [Epub ahead of print]53(2): 152466

Advances in the management of metastatic lobular breast cancer: Current evidence and emerging treatments.

Ana Isabel Martín-Quesada, Carla Martín-Abreu.

  Invasive lobular carcinoma (ILC) comprises ∼10%-15% of breast cancers and is characterized by loss of the cell-adhesion molecule E-cadherin (encoded by CDH1), discohesive growth, predominant estrogen receptor (ER) positivity, low-to-intermediate proliferation, and atypical metastatic spread to bone and gastrointestinal/peritoneal sites. Diagnostic assessment is often challenging owing to diffuse infiltration, frequently yielding non-measurable disease per response evaluation criteria in solid tumors (RECIST). Molecularly, ILC is enriched for phosphoinositide 3-kinase (PI3K) activation and harbors emerging vulnerabilities-such as ROS1 synthetic lethality in CDH1-deficient tumors and fibroblast growth factor receptor 1 (FGFR1)/bromodomain and extra-terminal (BET) dependencies-now under study. Because metastatic ILC remains underrepresented in trials, systemic therapy often mirrors invasive ductal carcinoma (IDC). This short communication synthesizes current evidence to distinguish shared from plausibly lobular-specific signals; highlights near-term opportunities-including antibody-drug conjugates (ADCs), oral selective ER degraders (SERDs), and selective use of immunotherapy in an immune-enriched subset with higher tumor-infiltrating lymphocytes (TILs) and PD-L1; and outlines trial-design adaptations-such as incorporating 18F-fluoroestradiol PET (FES-PET)-to improve representation and interpretability in metastatic ILC research.

Keywords:  Clinical trial design; E-cadherin loss; Endocrine therapy; Estrogen receptor positive; Metastatic invasive lobular carcinoma; PI3K/AKT/mTOR pathway; Peritoneal and gastrointestinal tract metastases; Underrepresentation

DOI:  https://doi.org/10.1016/j.seminoncol.2026.152466
J Immunother Cancer. 2026 Feb 24. pii: e013636. [Epub ahead of print]14(2):

Specific depletion of TIGIThigh CD226- clonally expanded intratumoral Tregs defines safe and effective TIGIT targeting.

Haoyue Zhou, Jinmei Li, Song Mei, Meiyu Zhang, Haochen Zhao, Kepeng Yan, Yumeng Cheng, Qunmin Zhou, Pan Zheng, Yang Liu, Peng Zhang, Hecheng Li, Wei Lv, Yan Zhang.

   BACKGROUND: Global clinical programs based on TIGIT (T cell immunoglobulin and ITIM domain) blockade have been terminated due to inadequate clinical efficacy. New approaches are needed to increase the antitumor activity of anti-TIGIT-based immunotherapy.
METHODS: Multiomics analyses, including single-cell RNA sequencing (scRNA-seq), single-cell TCR sequencing (scTCR-seq), and The Cancer Genome Atlas bulk RNA-seq, were performed to profile TIGIT and the costimulator CD226 expression and assess intratumoral regulatory T cells (Tregs) clonality, with validation by flow cytometry in murine and patient-derived tumor-infiltrating lymphocytes. The therapeutic efficacy of anti-TIGIT antibodies (αTIGIT), including αTIGIT-IgG1-wild-type (WT), αTIGIT-IgG1-WT with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity (αTIGIT-IgG1-ADCC), αTIGIT-IgG4-WT, and tiragolumab, was evaluated in MC38 tumors-inoculated humanized TIGIT knock-in mice (Tigith/h , Tigith/m ). Tumor microenvironment alterations were analyzed using flow cytometry and scRNA/TCR-seq. Antibody binding affinity and ADCC activity were assessed via biolayer interferometry and in vitro ADCC assays. Safety profiles were examined in a murine immune-related adverse events model through growth monitoring, survival analysis, and histopathological evaluation.
RESULTS: Using mouse models and clinical sample analysis, we identified a population of TIGIThigh CD226- clonally expanded intratumoral Tregs as a major barrier limiting the ability of TIGIT blockade to enhance effector cell function. αTIGIT-IgG1-ADCC specifically targeted and eliminated the TIGIThigh CD226- clonally expanded Treg subset, resulting in a marked improvement in antitumor efficacy compared with WT and clinically unsuccessful αTIGIT. Mechanistically, removal of these Tregs through αTIGIT-IgG1-ADCC relieved their suppression of stem-like CD4+ T cells, facilitating their differentiation into T helper cell 1 (Th1) effector cells. Th1-derived interferon-gamma (IFN-γ) further enhanced the functionality of tumor-infiltrating CD8+ T cells. Importantly, the presence of clonally expanded intratumoral Tregs and the suppression of stem-like CD4+ T cells correlated with poor immunotherapy response in patients with non-small cell lung cancer.
CONCLUSIONS: Targeted elimination of clonally expanded intratumoral Tregs is essential to unlock the full therapeutic potential of αTIGIT. These novel findings provide a key rationale and strategic direction for overcoming the limitations of current αTIGIT-based cancer immunotherapy.

Keywords:  Antibody; Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Immunotherapy; T regulatory cell - Treg

DOI:  https://doi.org/10.1136/jitc-2025-013636
Acad Radiol. 2026 Feb 20. pii: S1076-6332(26)00086-3. [Epub ahead of print]

CT-Based Radiomics Predicts the Functional State of Tumor-Infiltrating CD8+ T Cells and Prognosis in NSCLC.

Baojun Sang, Xiaoyu Zang, Jingkai Yu, Liying Yang, Guanqun Yang, Xiaodan Geng, Mei Zheng, Haoran Qi, Qingtao Qiu, Fanghan Cao, Ligang Xing, Xiaorong Sun.

   RATIONALE AND OBJECTIVES: The functional status of CD8+ T cells is a key factor influencing the prognosis in patients with non-small cell lung cancer (NSCLC). We aimed to develop a radiomics model predicting the functional state of tumor-infiltrating CD8+ T cells in NSCLC, explore semantic characteristics linking radiomic features to CD8+ T cell exhaustion, and establish a prognostic nomogram.
MATERIALS AND METHODS: A retrospective cohort of 256 patients with NSCLC undergoing radical resection with CD8+ T cell functional status determined by multiplex immunofluorescence staining was randomly divided 7:3 into training and validation sets. Radiomic features from preoperative contrast-enhanced CT scans were used to develop predictive models for high density of tumor center pre-dysfunctional CD8+ T cells (high-Tpre) and high density of invasive margin dysfunctional CD8+ T cells (high-Tdys) through least absolute shrinkage and selection operator, followed by semantic analysis. A nomogram for predicting recurrence-free survival integrated radiomics models with clinical characteristics.
RESULTS: Only the high-Tdys radiomics model was successfully established, yielding areas under the curve of 0.933 (training) and 0.792 (validation). Peritumoral imaging features on contrast-enhanced CT (fibrosis, inflammation, and atelectasis) were associated with CD8+ T cell exhaustion, evidenced by significantly higher high-Tdys proportions: 31.6% vs. 7.5% (P < 0.001), 35.6% vs. 8.1% (P < 0.001), and 40.0% vs. 11.8% (P = 0.028). The nomogram incorporating high-Tdys radiomics score, T stage, and N stage predicted 1- to 4-year predicting recurrence-free survival with areas under the curve of 0.733, 0.713, 0.637, and 0.600 (training), and 0.629, 0.669, 0.550, and 0.593 (validation).
CONCLUSION: Radiomics can predict the functional exhaustion of tumor-infiltrating CD8+ T cells in NSCLC, with specific imaging features associated with this process. Combining the radiomics model with clinical characteristics facilitates the assessment of patient prognosis.

Keywords:  CD8+ T cell exhaustion; NSCLC; Radiomics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.acra.2026.01.057
Cancer Discov. 2026 Feb 27.

Integrated chronic in vivo and in vitro screens uncover NFIL3 as a driver of T cell dysfunction.

Nayan Jain, Yuzhe Shi, Celina May, Sneha Mitra, Philip Bucher, Anton Dobrin, Zeguo Zhao, Sophie Hanina, Vinagolu K Rajasekhar, Yonghong Yao, Jorge Mansilla-Soto, Josef Leibold, Christina S Leslie, Francisco J Sanchez-Rivera, Judith Feucht, Michel Sadelain.

CAR therapy has transformed the treatment landscape for hematological malignancies but its efficacy in solid tumors is limited, owing in part to insufficient functional persistence of the engineered T cells. To elucidate the basis for their functional decline, we conducted integrated chronic in vivo and in vitro screens of 400 transcription factors, which revealed NFIL3 as a driver of CAR T cell dysfunction. Genetic disruption of NFIL3 in CAR T cells sustains their expansion, increases cytokine production, overall restraining terminal differentiation. Loss of NFIL3 enhances CAR T cell efficacy, improving tumor control and prolonging survival in xenograft and syngeneic mouse tumor models across different CAR designs. Under chronic stimulation, disruption of NFIL3 establishes a transcriptional state predictive of favorable clinical outcomes. Our findings underscore the power of comprehensive in vivo genetic screens integrated with multi-parameter in vitro assessment and identify NFIL3 as a novel therapeutic target to enhance cancer immunotherapy.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1524
Biofabrication. 2026 Feb 24.

Characterization of a hybrid hydrogel for the studying of lymphocyte infiltration and migration in a 3-dimensionalin vitrotumor stroma device.

Marco Antonio Rodriguez, Saeed Derakhshesh, Mejalaa Mega Jayaseelan, Johan Rosgaard, Alexander Chin Poh, Gennaro Longobardo, Thomas DePalma, Aleksander Skardal.

  Solid tumors reprogram their surrounding microenvironment to develop a tumor promoting and immunosuppressive niche of cells and extracellular matrix known as the tumor stroma. While many successful immunotherapies modulating the use of cytotoxic lymphocytes have been established, success in solid tumors has been limited, in part due to the stroma disrupting T cell infiltration and/or migration into the tumor boundary, thereby obstructing their contact with cancer cells. There exists a need for the development of three-dimensional tissue engineered models to better understand the mechanisms of infiltration and migration of solid tumors by cytotoxic lymphocytes. Here we present the validation of a three-dimesional hydrogel system, implemented into a tumor-on-a-chip device, allowing for the observation of infiltration and migration of T cells, in addition to the influence that tumor cells have on stromal fibroblasts. This hydrogel allows for greater infiltration of T cells compared to other formulations. Differences in migration are observed depending on lymphocyte type. Fibroblasts are influenced towards a cancer-associated fibroblast morphology with increased alpha-smooth muscle actin expression, and are seen to modify their spatial orientation relative to A375 melanoma cells. Finally fibroblast presence in the hydrogel inhibits infiltration of T cells. Combined, these results validate the application of this model to study lymphocyte infiltration and migration into solid tumors. Future modulation of cell populations, along with the integration of patient derived samples, can provide a system to test immunotherapy effectiveness for cancer patients.

Keywords:  Melanoma; Microphysiological Systems; Organ-on-a-chip; Solid Tumors; Solid Tumors Tumor Stroma Melanoma Organ-on-a-chip Microphysiological Systems; Tumor Stroma

DOI:  https://doi.org/10.1088/1758-5090/ae49fd
Front Pharmacol. 2026 ;17 1722027

Piezo1 as a mechanical checkpoint in T cell immunotherapy for solid tumors.

Xinmu Cui, Jianan Zhao, Huajie Tian.

  T cell-based immunotherapies exhibit limited efficacy against solid tumors, a challenge primarily attributed to the immunosuppressive and mechanically hostile tumor microenvironment (TME). Within this context, the mechanosensitive ion channel Piezo1 has emerged as a key TME mechanosensor, yet its role in modulating T cell-mediated anti-tumor immunity remains to be fully elucidated. This review aims to synthesize existing evidence on Piezo1's regulation of T cell functions, including activation, proliferation, and infiltration, and its broader impact on immunotherapy for solid tumors. We highlight Piezo1's dual regulatory function in the immune landscape: acute activation robustly enhances T cell effector functions and cytotoxicity, whereas chronic stimulation within the stiff TME paradoxically promotes T cell exhaustion. Importantly, preclinical studies demonstrate that modulating Piezo1 signaling, particularly in combination with matrix normalization synergistically enhances the infiltration, persistence, and overall antitumor efficacy of adoptive T cells and endogenous immune responses. These findings position Piezo1 as a promising mechanical checkpoint for improving T cell therapies. Nevertheless, significant challenges persist for clinical implementation, including the heterogeneity of mechanical signals and the pleiotropic nature of Piezo1 across different cell types. Future research should therefore focus on developing T cell-specific mechanotherapies, identifying novel targets, and validating mechanical biomarkers to guide patient stratification, thereby accelerating the clinical translation of "mechanoimmunology".

Keywords:  Piezo1; T cell exhaustion; T cells; chimeric antigen receptor (CAR)-T cells; mechanoimmunology; solid tumors; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fphar.2026.1722027
Front Med (Lausanne). 2026 ;13 1656289

Circulating ex-Trm CD8 + T cells with skin-homing/chemoattraction phenotype are associated with disease severity in atopic dermatitis.

Maria F Ordóñez-Rubiano, Miguel Parra, Diana Bautista, Consuelo Romero-Sánchez.

   Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by skin-homing memory T cells. Recent evidence suggests that a subset of tissue-resident memory T (Trm) cells can exit tissues and recirculate as ex-Trm cells.
Methods: Peripheral blood memory T cell subpopulations were analyzed in adults with AD, stratified by disease severity, using multiparametric flow cytometry. CD4+ and CD8+ memory subsets and the skin-homing markers CLA, CCR4, and CCR10 were evaluated.
Results: Overall CD4+ and CD8+ memory T cell distributions were preserved. AD patients showed expansion of CD4+ central memory T cells expressing CLA, CCR4, and CCR10. Most notably, a circulating population of CD8+ ex-Trm cells co-expressing CLA, CCR4, and CCR10 was increased in moderate-to-severe disease and correlated positively with clinical severity. No comparable expansion was observed for CD4+ ex-Trm cells.
Discussion: Circulating CD8+ ex-Trm cells with skin-homing properties may contribute to AD progression by reseeding distant skin sites and sustaining inflammation, whereas CD4+ ex-Trm cells may remain preferentially retained within inflamed skin. These findings identify circulating CD8+ ex-Trm cells as potential biomarkers of disease severity and disease dissemination.

Keywords:  CLA; atopic dermatitis; atopic eczema; memory T cells; memory T lymphocytes

DOI:  https://doi.org/10.3389/fmed.2026.1656289
Sci Rep. 2026 Feb 26.

Pretreatment tumor infiltrating lymphocytes and outcome in patients with HR+/HER2- advanced breast cancer treated with CDK4/6 inhibitors.

Rosalba Torrisi, Laura Giordano, Saverio Pancetti, Carlo Carnaghi, Vera Basilico, Raffaella Palumbo, Riccardo Gerosa, Giuseppe Saltalamacchia, Maria Vita Sanò, Armando Santoro, Bethania Fernandes.

  Growing evidence suggests that enhancement of the tumor immune response contributes to the antitumor activity of CDK4/6 inhibitors (CDK4/6i), but the role of pretreatment tumor immune microenvironment is not clear. We retrospectively investigated in patients with HR+/HER2- advanced breast cancer receiving CDK4/6i and endocrine therapy whether pretreatment stromal tumor infiltrating lymphocytes (sTILs) were associated with outcome. A total of 100 patients were evaluable 53 treated with palbociclib, 44 with ribociclib and 3 with abemaciclib. Tumors were classified as sTILs positive (sTILs+) when sTILs were ≥ 10%. 58 tumors were sTILs negative (sTILs-) and 42 sTILs+. sTILs were not associated with any outcome overall and in the ribociclib cohort. Conversely, patients treated with palbociclib and sTILs+ tumors experienced a statistically significant improved overall survival (mOS Not Reached vs. 41.1 months, p = .038) and a reduced risk of visceral progression (24 vs. 8 patients p=.0048) as compared with patients with sTILs- tumors. Pretreatment sTILs levels were associated with outcome in patients treated with palbociclib. Given the lack of interaction between treatment and sTILs our findings warrant validation in larger, independent cohorts and if confirmed propose sTILs as a simple and reproducible biomarker to aid patient selection for palbociclib.

Keywords:  CDK4/6 inhibitors; HR+/HER2 negative advanced breast cancer; Stromal tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1038/s41598-026-40616-1
bioRxiv. 2026 Feb 12. pii: 2026.02.10.704454. [Epub ahead of print]

A Framework for Comparing Mouse Neoantigen Immunogenicity.

Peter J Matulich, Carly N Sprague, Victoria P Schuster, Alyssa M Granados, Rohan B Chaudhari, Megan L Burger.

Cytotoxic CD8+ T cell responses targeting tumor neoantigens are critical for immunotherapy efficacy and are widely studied across different preclinical mouse tumor models. Defined neoantigens are commonly introduced to enable tracking of tumor-specific T cells; however, variation in neoantigen choice may yield immune phenotypes attributable to differences in neoantigen immunogenicity, complicating interpretation of tumor-intrinsic mechanisms. Here, we determined the relative immunogenicity of a set of 25 commonly used mouse tumor-derived and model neoantigens to facilitate comparison of neoantigens across studies. We found that in silico predicted major histocompatibility complex (MHC) binding affinity poorly stratified in vivo immunogenicity. In contrast, experimental measurement of peptide-MHC complex stability (K off ), more so than measured affinity (K D ), closely correlated with the relative magnitude of neoantigen-targeted vaccine responses in vivo . Thus, we report the relative stability of a known set of commonly used neoantigens as a reference and provide a simple method to benchmark novel neoantigens against this library. This framework will allow contextualization of the level of immunogenicity of newly identified neoantigens and aid in comparative interpretation of tumor-immune phenotypes across studies.

DOI: https://doi.org/10.64898/2026.02.10.704454
Cell Chem Biol. 2026 Feb 25. pii: S2451-9456(26)00033-4. [Epub ahead of print]

Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells.

Jianfeng Pang, Zengge Wang, Cuixia Yang, Lin Huang, Yiran Qiu, Hui Wang, Keling Huang, Xiaoxue Li, Zifeng Yang, Hudan Pan, Liang Liu, Xuemei Tong, Bin Li, Mingjun Zhang, Lin Zhong, Zhigang Li, Feng Wang.

  Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8+ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8+ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.

Keywords:  CD8(+) T cell; NQO1; antitumor immunity; glucose metabolism; lawsone; metabolic reprogramming; mitochondrial ROS; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.chembiol.2026.02.001
Cancer Immunol Immunother. 2026 Feb 28. pii: 89. [Epub ahead of print]75(3):

Integrative analysis of T cell subset-specific ICOS expression and tumor HLA class I/II expression in lung adenocarcinoma: implications for their interaction and clinical outcome.

Hiroyuki Yamada, Rin Yamada, Yoshihiro Komohara, Cheng Pan, Daiki Yoshii, Hiromu Yano, Eri Matsubara, Yusuke Shinchi, Hirotake Tsukamoto, Yukio Fujiwara, Koei Ikeda, Makoto Suzuki.

   OBJECTIVES: Inducible T cell costimulator (ICOS) is a CD28-family costimulatory receptor with bidirectional therapeutic effects on antitumor immunity, and HLA-mediated tumor recognition is essential for effective T cell responses. However, their clinicopathological significance in lung adenocarcinoma (LUAD) is not fully understood. We investigated subset-specific pattern of ICOS expression and examined whether ICOS+ tumor-infiltrating lymphocyte (TIL) density and tumor HLA expression provide immune context and prognostic information in LUAD.
MATERIALS AND METHODS: We examined 228 resected LUADs by immunohistochemistry. ICOS+ TIL density and HLA class I and HLA-DR status were compared with the densities of CD8+, CD3+CD8-, and FOXP3+ TILs and with postsurgical outcomes. Subset-specific ICOS expression was evaluated using multiplex pseudocolored immunohistochemistry in 10 representative cases selected from the ICOS+ TIL-high group and validated using a publicly available single-cell RNA-seq dataset.
RESULTS: ICOS+ TIL density correlated with each T cell subset. Multiplex analysis showed the highest ICOS positivity among Tregs, followed by CD4+ non-Tregs and CD8+ TILs. Because CD4+ non-Tregs were numerically predominant, ICOS+CD4+ non-Tregs constituted the largest ICOS+ fraction. Single-cell RNA-seq analysis corroborated these findings. ICOS+ TIL density was significantly higher in HLA-DR-strong tumors, and tumor HLA class I and HLA-DR were associated with longer recurrence-free survival. ICOS had no overall prognostic impact; however, among HLA-DR-strong tumors, ICOS-high patients tended toward longer cancer-specific survival.
CONCLUSION: In LUAD, ICOS+ TIL density largely reflects ICOS+CD4+ non-Treg infiltration and is enriched in HLA-DR-strong tumors. Tumor HLA expression was associated with favorable prognosis, and ICOS may have context-dependent clinical significance that warrants further investigation.

Keywords:  CD278; HLA class I; HLA class II; Inducible T cell costimulator; Lung adenocarcinoma; Tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s00262-026-04327-w
Cancer Immunol Res. 2026 Feb 25.

VSIG4 restricts hepatocellular carcinoma control by suppressing tumor-specific CD8+ T cell immunity in the tumor microenvironment.

Jinglong Guo, Siddheshvar Bhela, Monica Sharma, Giulia Protti, Shiuh-Ming Luoh, Siyue Wang, Natalie S Firmino, Dragos C Dasoveanu, Caleb Chan, Veronica Ibarra-Lopez, Conrad Foo, Rajiv Jesudason, Sandra Rost, Tina Scholl, James Ziai, Laetitia Comps-Agrar, Yulei Wang, Sören Müller, Andrey S Shaw, Jing Li, Shannon J Turley, Wenxian Fu.

Immunotherapies have revolutionized the treatment of hepatocellular carcinoma (HCC), yet their response rates remain limited, highlighting the need for new therapeutic targets. In this study, we found that VSIG4 (V-set and immunoglobulin domain containing 4) is predominantly expressed by macrophages in both mouse and human HCC, with high VSIG4 expression correlating with poor prognosis in HCC patients. In autochthonous HCC models, VSIG4 deficiency in mice promoted tumor-specific CD8+ T cell abundance, intratumoral infiltration, and effector function in the tumor microenvironment, resulting in better tumor control and significantly enhanced efficacy of anti-PD-L1 and anti-VEGF combination treatments. Furthermore, we observed that VSIG4+ macrophages colocalize with CD8+ T cells in HCC, and that VSIG4 directly mediates T cell suppression in ex vivo and in vitro studies. These findings suggest that VSIG4 is a critical inhibitor of anti-tumor immunity in HCC and may be targeted for improved immunotherapies.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0836
Cancers (Basel). 2026 Feb 19. pii: 680. [Epub ahead of print]18(4):

The Proximity of PD-1-CD103+ Tissue-Resident CD8+ T Cells to Tumor Cells Is Correlated with Improved Clinical Outcomes in Patients with Cholangiocarcinoma.

Zhenyu Li, Danping Liu, Jingjing He, Junrui Ma, Muyuan He, Xiaobao Yang, Yanan Zhao, Xuefeng Fei, Dakang Xu, Mengjie Deng.

  Background/Objectives: Cholangiocarcinoma (CCA) is characterized by a heterogeneous immune microenvironment, where the prognostic significance of CD8+ tissue-resident memory T (TRM) cell activation and spatial positioning remains to be fully elucidated. This study investigated how the activation phenotypes and their spatial distribution relative to tumor cells influence anti-tumor immunosurveillance and predict clinical outcomes in CCA. Methods: Multiplex immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq) were employed to characterize naïve (PD-1-CD103+CD8+) and exhausted (PD-1+CD103+CD8+) subsets. G-cross function analysis was utilized to quantify the spatial proximity between these specific TRM subsets and tumor cells, correlating the spatial interaction with patient overall survival. Results: scRNA-seq profiling revealed that PD-1-CD103+CD8+ TRM cells were enriched in genes associated with lymphocyte activation and cytotoxicity, while PD-1+CD103+CD8+ TRM cells exhibited an exhaustion signature. Spatially, PD-1-CD103+CD8+ TRM cells exhibited increased interactions with tumor cells, whereas PD-1+CD103+CD8+ TRM cells showed reduced engagement. Therefore, the close proximity of PD-1-CD103+CD8+ TRM cells to tumor cells was identified as a significant predictor of favorable clinical outcomes. Conclusions: The activation state of CD8+ TRM cells combined with their spatial localization constitutes a critical prognostic factor in CCA. Effective anti-tumor immunosurveillance relies on the direct engagement of naïve TRM cells with tumor cells. These findings highlight the potential of PD-1-targeted immunotherapies to remodel the spatial proximity of the tumor microenvironment, potentially promoting the redistribution of effector cells into tumor-proximal regions.

Keywords:  CD103+CD8+ tissue-resident T cells; G-cross; PD-1 expression; cholangiocarcinoma; spatial interaction

DOI:  https://doi.org/10.3390/cancers18040680
Immunity. 2026 Feb 26. pii: S1074-7613(26)00085-3. [Epub ahead of print]

Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.

Dayana B Rivadeneira, Sanjana Thosar, Kevin Quann, William G Gunn, Victoria G Dean, Bingxian Xie, Angelina Parise, Andrew C McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P Barnes, Marcel P Bruchez, Patricia L Opresko, Greg M Delgoffe.

DOI: https://doi.org/10.1016/j.immuni.2026.02.015
Nat Rev Cardiol. 2026 Feb 23.

Cardiotoxicity of T cell immunotherapies.

Michael A Raddatz, Ashley F Stein-Merlob, Syed S Mahmood, Sarju Ganatra, Daniel Addison, Tasha L Lin, Sarah M Larson, Eric H Yang.

T cell immunotherapies offer a new approach to cancer therapy. Chimeric antigen receptor (CAR) T cell therapy is the most prolific of these treatments, leveraging genetically engineered T cells to augment the antitumour response. Bispecific antibodies, T cell receptor-engineered T cells and tumour-infiltrating lymphocytes have also emerged as novel T cell therapies with therapeutic benefit. As the variety of T cell therapies and indications for their use expand, a nuanced understanding of potential haemodynamic sequelae and cardiovascular toxicities is required. T cell activation can lead to massive cytokine release and excessive inflammation, termed cytokine release syndrome (CRS). Like other inflammatory syndromes, CRS can lead to cardiovascular complications, including arrhythmias, myocardial infarction and heart failure, with an incidence of cardiovascular events as high as 20% among patients who develop high-grade CRS. In this Review, we summarize the mechanisms, epidemiology and management of T cell therapy-associated CRS and subsequent cardiotoxicity. We also explore how an improved understanding of CAR T cell therapy, and other emerging T cell-based treatments, will inform the prevention and management of adverse cardiovascular events.

DOI: https://doi.org/10.1038/s41569-026-01265-z
Am J Transplant. 2026 Feb 21. pii: S1600-6135(26)00103-6. [Epub ahead of print]

Identification of a Highly Functional Effector CD8+ T Cell Program after Transplantation in Mice and Humans.

Riley P Leathem, Joel S Freibaum, Gregory S Cohen, Robin Welsh, Yukai Tang, Marina W Shirkey, Sanniddhya B Bardhan, Ryo Hatano, Chikao Morimoto, Byoung Chol Oh, Daniela Čiháková, Jonathan S Bromberg, Scott M Krummey.

  To better understand the mechanism by which T cells mediate allograft rejection, we investigated the fate and function of graft-specific CD8+ T cells expressing the activated isoform of CD43 in mice and humans. Agonism of the CD43 1B11 receptor in vitro induced CD8+ T cell proliferation in the presence of sub-threshold antigen stimulation, and CD43 1B11 agonism in vivo overcame costimulation-blockade induced tolerance and enhanced CD8+ T cell cytokine production and cytotoxic function. Effector CD43 1B11+ CD8+ T cells expressed high levels of T-bet, but also maintained IL-7Rα, and TCF-1 expression at both effector and memory timepoints. In adoptive transfer experiments, CD43 1B11+ CD8+ T cells were persistent following graft rechallenge and also formed TCF-1+IL-7Rα+ memory cells. Human CD8+ T cells expressing CD43 and the glycosyltransferase GCNT1 were present in rejecting kidney allografts and had high expression of IFNG, ICOS, and perforins/granzymes. In healthy human donors and transplant candidates, the CD43 1D4 mAb clone defined antigen-experienced cytokine-producing CD8+ T cells. In sum, these data support an important role for activated CD43+ CD8+ T cells as potent effectors, and point to a potential role for CD43 1B11 signaling in augmenting effector functions in the context of sub-threshold antigen or costimulation.

Keywords:  alloimmunity; costimulation blockade; effector CD8(+) T cells; tolerance

DOI:  https://doi.org/10.1016/j.ajt.2026.02.020
J Magn Reson Imaging. 2026 Feb 22.

Diffusion Relaxation-Correlated Spectroscopic MR Imaging for In Vivo Tumor Heterogeneity and Lymph Node Metastasis Prediction in Oral Tongue Squamous Cell Carcinoma.

Dongmei Wu, Siyu Li, Wentao Hu, Huihao Xu, Qiuhong Liu, Peng Hu, Yingwei Wu, Yongming Dai.

   BACKGROUND: In oral tongue squamous cell carcinoma (OTSCC), cervical lymph node metastasis (CLNM) reduces predicted survival by 50%. However, MRI sensitivity for occult nodal disease is only 35.7%, reflecting limited microstructural specificity.
PURPOSE: To investigate whether diffusion-relaxation correlated spectroscopic imaging (DR-CSI) metrics with peritumoral extensions contribute toward the prediction of CLNM in OTSCC.
STUDY TYPE: Prospective.
POPULATION: 99 patients (33 female and 66 male) with pathologically confirmed OTSCC.
FIELD STRENGTH/SEQUENCE: 3T; a spin-echo echo-planar DR-CSI with 35 contrasts.
ASSESSMENT: Tumor-stroma ratio (TSR), density of tumor-infiltrating lymphocytes (TILs), perineural invasion (PNI) and differentiation status were determined from histology. Tumor greatest diameter and depth of invasion (DOI) were evaluated from MRI. Apparent diffusion coefficient (ADC) maps and T2 maps were derived from DR-CSI data. Five DR-CSI compartmental metrics in intratumoral and peritumoral regions, VA-VE, were calculated.
STATISTICAL TESTS: Mann-Whitney U-test, Chi-square test, or Spearman correlation analysis. Multivariable logistic regression and receiver operating characteristic (ROC) analysis for diagnostic performance. Significance criteria: p < 0.05.
RESULTS: 51 patients were CLNM negative. Intratumoral VA in the CLNM-positive group (34.80% ± 18.51%) was significantly lower than that in the CLNM-negative group (47.86% ± 23.37%), while VB (25.07% ± 12.49%) and VD (22.12% ± 11.46%) in the CLNM-positive group were significantly higher than those in the CLNM-negative group. ADC and T2 showed no significant separation (p = 0.084, 0.493, respectively). A multivariable logistic model comprising the significant intratumoral and peritumoral DR-CSI metrics (VA, VB, and VD) together with the morphologic variables (tumor greatest diameter and DOI) achieved an area under curve (AUC) value of 0.792 for CLNM classification, representing a non-significant improvement over the morphologic variables model alone (AUC 0.709, p = 0.069).
DATA CONCLUSION: The intratumoral and peritumoral DR-CSI metrics, combined with morphologic variables, improved preoperative discrimination of nodal status in OTSCC in this single center cohort, though external validation is warranted.
EVIDENCE LEVEL: 2.
TECHNICAL EFFICACY: Stage 2.

Keywords:  diffusion; lymph node metastasis; magnetic resonance imaging; oral tongue squamous cell carcinoma; tumor heterogeneity

DOI:  https://doi.org/10.1002/jmri.70273
Cell Death Dis. 2026 Feb 26.

PD-1 protects expanding human T cells from premature restimulation-induced cell death by modulating TCR and CD28 signaling.

Katherine P Lee, Sara Elster, Benjamin Epstein, Camille M Lake, Andrew L Snow.

Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on T cells that dampens TCR and CD28 signaling in the immunological synapse. PD-1 is significantly upregulated on T cells in the tumor microenvironment, where it promotes exhaustion in the context of chronic antigen restimulation. Exhaustion renders T cells hyporesponsive and ineffectual, but potentially resistant to restimulation-induced cell death (RICD). Restimulation-induced cell death (RICD) is a critical propriocidal apoptosis program triggered in activated T cells upon robust TCR re-engagement, which serves to constrain effector T cell expansion and longevity to prevent collateral tissue damage. While the checkpoint function of PD-1 has profound implications for cancer immunotherapy, the role of PD-1 in regulating newly activated T cells remains unclear. We hypothesized that PD-1 attenuates RICD sensitivity in human effector T cells by modulating TCR signal strength. Here we show that transient upregulation of PD-1 helps to protect clonally expanding human CD4+ and CD8 + T cells from premature RICD, with only moderate protection noted in terminally-differentiated, PD-1lo effector CD8 + T cells. Restimulation of T cells with beads containing PD-L1 results in significant apoptosis resistance, dependent on PD-L1 dosage and the proximity of PD-L1 to the TCR and CD28. Interestingly, PD-L1 demonstrated a more significant RICD rescue with CD28 co-ligation as opposed to TCR engagement alone, suggesting PD-1 signaling targets both signaling pathways in this context. Furthermore, biochemical/proteomic data suggest PD-1 modulates proximal signaling downstream of both TCR and CD28 and influences the expression of specific pro/anti-apoptotic proteins that govern RICD sensitivity. Despite the original assumption of PD-1 as a programmed death-inducing protein, our research reveals that homeostatic expression of PD-1 in clonally expanding T cells confers RICD resistance that promotes T cell survival and persistence. These findings present significant implications for understanding how blocking or engaging the PD-L1:PD-1 signaling axis may influence apoptosis sensitivity in both normal and exhausted T cells to alter adaptive immune responses.

DOI: https://doi.org/10.1038/s41419-026-08530-6
World J Surg Oncol. 2026 Feb 23.

Comparative analysis of clinicopathological characteristics and prognosis between E-cadherin-negative breast lymphoepithelioma-like carcinoma and E-cadherin-negative invasive lobular carcinoma.

Rui Gao, Xi Zhang, Ying Lin, Jie Lin, Yihui He, Lan Lin, Ran Peng, Xin Chen.

   BACKGROUND: E-cadherin-negative breast lymphoepithelial-like carcinoma (E-Cad-neg BLEC) is a rare malignant tumor. To date, no study has compared the clinicopathological characteristics and prognosis between E-Cad-neg BLEC and E-Cad-neg invasive lobular carcinoma (ILC).
METHODS: To clarify the relationship between E-Cad-neg BLEC and E-Cad-neg ILC, we analyzed 12 patients with E-Cad-neg BLEC, comparing their clinicopathological characteristics and tumor prognosis with those of 578 patients with E-Cad-neg classical invasive lobular carcinoma (c-ILC) or 43 patients with E-Cad-neg pleomorphic lobular carcinoma (PLC).
RESULTS: The results showed that E-Cad-neg BLEC was a diffuse, non-adherent tumor with pleomorphic growth. There was abundant lymphocyte infiltration in the tumor stroma. Lobular carcinoma in situ was observed around the tumor in 5 patients. Compared with E-Cad-neg c-ILC, E-Cad-neg BLEC had significantly lower expression levels of ER (p < 0.001), PR (p < 0.001), and HER2 (p = 0.029), and a higher Ki-67 proliferation index (p < 0.001). Compared with E-Cad-neg PLC, E-Cad-neg BLEC was less likely to exhibit vascular invasion (p < 0.001) and perineural invasion (p < 0.001), and had lower HER2 expression (p = 0.001). In terms of histo-molecular subtypes, E-Cad-neg BLEC was mainly triple-negative, while E-Cad-neg c-ILC and E-Cad-neg PLC were mainly luminal A and luminal B. Regarding prognosis, the prognosis curve of E-Cad-neg BLEC was close to that of E-Cad-neg c-ILC. Analysis of the percentage of tumor-infiltrating lymphocytes (TILs) revealed that in both E-Cad-neg c-ILC and E-Cad-neg PLC, higher TIL levels were associated with a poor prognosis, in contrast to the favorable prognosis observed in E-Cad-neg BLEC.
CONCLUSIONS: Our findings indicate that E-Cad-neg BLEC is a type of breast carcinoma characterized by extensive lymphocytic infiltration and high proliferative activity and is associated with a relatively favorable prognosis.

Keywords:  Breast lymphoepithelial-like carcinoma; E-cadherin; Invasive lobular carcinoma; Pleomorphic lobular carcinoma; Prognosis

DOI:  https://doi.org/10.1186/s12957-026-04263-0
Adv Sci (Weinh). 2026 Feb 27. e19765

DADA Enhances CD8+ T Cell Stemness to Improve Anti-Tumor Immunity and Immunotherapy Efficacy.

Mingyue Bi, Fei Li, Heng Jiang, Lingling Gu, Mengjie Sun, Kunyu Lu, Pianpian Liu, Ruyue Xie, Wenqiang Ma, Meijuan Zheng, Xianwei Wang, Xuefu Wang, Jingjing Cong.

  Progenitor exhausted CD8+ T (Tpex) cells have recently been identified as a stem-like T cell subset that mediates durable anti-tumor immune responses and represents a pivotal population responsive to immunotherapies. Here, it is demonstrated that diisopropylamine dichloroacetate (DADA) facilitates CD8+ T cell-mediated anti-tumor immunity and promotes Tpex cells accumulation in the tumor microenvironment. Mechanistically, DADA promotes the conversion from pyruvate to Acetyl-CoA by inhibiting pyruvate dehydrogenase kinase. This process leads to increased oxidative phosphorylation (OXPHOS) and mitochondrial fitness, thereby enhancing CD8+ T cells stemness. Treatment of mice with DADA improves the efficacy of PD-1 blockade. Furthermore, the in vitro expansion of chimeric antigen receptor (CAR)-T cells supplemented with DADA confers them with stemness characteristics, contributing to improved anti-tumor efficacy. Collectively, this study illustrates how DADA-mediated metabolic reprogramming in CD8+ T cell enhances their stemness, underscoring its potential for anti-tumor therapy.

Keywords:  CD8+ T cell; anti‐tumor immunity; metabolic reprogramming; stemness

DOI:  https://doi.org/10.1002/advs.202519765
Cell Rep. 2026 Feb 25. pii: S2211-1247(26)00113-0. [Epub ahead of print]45(3): 117035

Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.

Yi Wang, Chao Huang, Guoxin Cai, Massimo Andreatta, Armand Kurum, Yang Zhao, Bing Feng, Min Gao, Santiago J Carmona, Zhan Zhou, Cheng Sun, Yugang Guo, Li Tang.

  Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy. However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy. Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely and effectively reprograms NK cell metabolism and restores their effector function in vivo. IL-21-Fc synergizes with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer to eradicate MHC class I-deficient tumors and confer durable protection across multiple murine models. Mechanistically, we uncover that IL-21-Fc enhances NK cell effector function by upregulating glycolysis in a lactate dehydrogenase A (LDHA)-dependent manner. This study reveals LDHA-dependent metabolic reprogramming as a key axis for NK cell rejuvenation and positions IL-21-Fc as a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.

Keywords:  CP: cancer; CP: metabolism; LDHA; MHC class I-deficient tumor; NK cell exhaustion; NK cell therapy; cancer immunotherapy; glycolysis; immunometabolism; interleukin 21

DOI:  https://doi.org/10.1016/j.celrep.2026.117035
Cancer Discov. 2026 Feb 19. OF1

"Armoring" CAR T Cells Bolsters Activity against Solid Tumors.

Two recent studies of CAR T cells targeting tumor-associated macrophages have shown that "armoring" these engineered cells with the ability to express the cytokine IL12 makes them more effective at eradicating solid tumors and leads to sustained remodeling of the immunosuppressive tumor microenvironment.

DOI: https://doi.org/10.1158/2159-8290.CD-NW2026-0016
Cell Oncol (Dordr). 2026 Feb 24. pii: 48. [Epub ahead of print]49(2):

Discover personalized drug opportunity and optimized tumor-infiltrating lymphocyte therapy for rare cancer: an organoid-based whole-journey clinical mapping study in a neuroendocrine cancer patient.

Xinyu Gao, Zhenjiang Liu, Zhaoting Xu, Ke Liu, Yiming Zhang, Jing Yu, Xu Wang, Xinghua Cheng, Chao Ni, Pin Wang, Yarong Liu, Xinfang Hong, Jingwei Sun, Bing Zhao.



Keywords:  Clinical trial; Immune co-culture; Organoids; Rare cancer; Tumor evolution; Tumor-infiltrating lymphocyte therapy; Whole clinical journey case study

DOI:  https://doi.org/10.1007/s13402-026-01172-y
Ann Am Thorac Soc. 2026 Feb 25. pii: aaoag043. [Epub ahead of print]

A woman with hypoxemia and bilateral alveolar opacities following tumor-infiltrating lymphocyte and interleukin-2 infusion.

Marcos Vinicius Fernandes Garcia, Daniel Gergen, Marika Orlov.

DOI: https://doi.org/10.1093/annalsats/aaoag043
Vet Comp Oncol. 2026 Feb 25.

CD30 Expression in Neoplastic Mast Cells and the Presence of CD30+, CD3+, and PAX-5+ Tumour-Infiltrating Lymphocytes as Prognostic Markers in Canine Cutaneous Mast Cell Tumours.

Fernanda Ramalho Ramos, Janayna Maria Parente Serafim, Bethânia Almeida Gouveia, Pedro Luiz Porfirio Xavier, Juliano Rodrigues Sangalli, Heidge Fukumasu, Ricardo de Francisco Strefezzi.

  Canine cutaneous mast cell tumour (MCT) is the most common skin neoplasm in dogs, with histopathology serving as both the diagnostic and primary prognostic tool. However, identifying reliable biomarkers is essential for improving clinical decision-making. CD30, a member of the TNF receptor superfamily, is well-characterised in human haematopoietic malignancies. However, its role in canine MCTs remains unclear. This study aimed to evaluate CD30 expression in neoplastic mast cells and tumour-infiltrating lymphocytes (TILs), and to assess its prognostic significance in canine cutaneous MCTs. Immunohistochemical analysis of CD30, CD3, and PAX-5 was performed on 53 samples, and RNA sequencing was conducted to assess CD30 transcript levels in 17 cases. CD30 was detected in 94.6% of neoplastic mast cells, with strong staining observed in 35 cases and weak staining in 18. Strong CD30 expression (p = 0.0051), CD30+ TIL counts (p = 0.0105) and the diffuse infiltrate distribution pattern of CD3+ TILs (p = 0.0497) were associated with shorter post-surgical survival. RNA sequencing confirmed higher CD30 (TNFRSF8) gene expression levels in high-risk tumours (logFC = 2.3182; FDR = 0.0405). These findings suggest that CD30 is a promising biomarker with potential prognostic value in canine cutaneous MCTs.

Keywords:  TNFRSF8; cancer; immunohistochemistry; mast cells; prognosis

DOI:  https://doi.org/10.1111/vco.70058
Nat Med. 2026 Feb 27.

Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial.

Jan-Jaap J Mellema, Chantal F Stockem, Cameron Herberts, Samantha K Cheung, Daniel J Vis, Bas W G van Rhijn, Laura S Mertens, Thierry N Boellaard, Maurits L van Montfoort, Sara Balduzzi, Jeantine M de Feijter, Johannes C K van der Mijn, Shruti Sharma, Adam C El Naggar, Joost L Boormans, Martine Franckena, Richard P Meijer, Juus L Noteboom, Eva E Schaake, Debbie G J Robbrecht, Britt B M Suelmann, Michiel S van der Heijden.

Radical cystectomy is the most commonly used definitive local treatment for muscle-invasive bladder cancer (MIBC), yet it carries substantial perioperative complication risk, alongside major changes in urinary and sexual function. Chemoradiotherapy (CRT) is used as a bladder-sparing alternative but is usually reserved for small, solitary tumors. Highly active systemic induction therapy could enable bladder preservation for patients with more advanced tumors and reduce recurrence risk. We previously demonstrated high activity of preoperative ipilimumab (3 mg kg-1) plus nivolumab in patients with stage III MIBC. Given this high activity, the single-arm, multicenter phase 2 INDIBLADE trial aimed to provide effective bladder-sparing treatment to patients with stage II/III (cT2-4aN0-2, n = 50) MIBC, using induction ipilimumab (3 mg kg-1) plus nivolumab followed by CRT. After a median follow-up of 28.7 months, the primary endpoint of estimated 2-year bladder-intact event-free survival (BI-EFS) was met at 78% (95% confidence interval (CI): 0.67-0.9, P < 0.001). Secondary endpoints included overall survival, safety and the predictive value of circulating tumor DNA (ctDNA). Two-year overall survival was 96% (95% CI: 0.91-1). Grade 3-4 immune-related adverse events occurred in 24% of patients; grade 3-4 CRT-related adverse events occurred in 7% of patients. Absence of detectable ctDNA after induction immunotherapy was associated with BI-EFS (hazard ratio 8.3, 95% CI: 1.38-50.36, P = 0.02). In conclusion, our results show that induction combination immunotherapy followed by CRT is an effective bladder-sparing treatment in MIBC, and response can be monitored by ctDNA. ClinicalTrials.gov identifier: NCT05200988 .

DOI: https://doi.org/10.1038/s41591-026-04271-3