bims-tuinly 2026-10-18 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–10–18
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Clinicopathological Features of DLL3 Expression and T-Cell Infiltration in LCNEC: Insights From Pathology and Clinical Response to Tarlatamab.
TILs in Breast Cancer: Paving New Ways Beyond Their Prognostic and Predictive Values.
Value of Breast and Axillary Tumor-Infiltrating Lymphocytes for Response to Neoadjuvant Chemo-(Immuno)Therapy in Clinically Node-Positive Breast Cancer.
Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review.
Evaluation of MRI Radiomic Features as Surrogates of Tumor Immune Status in Breast Cancer: A Pilot Study of MRI-Derived Radiomic Features for Non-Invasive Immune Profiling in Breast Cancer.
Clinical trial landscape and translational priorities for adoptive T-cell and NK-cell therapies in gynecologic malignancies.
Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives.
CRISPR-Cas9 screen identifies eIF4G2 as a regulator of CD8+ T cell dysfunction.
Selective expansion of neoantigen-specific peripheral blood lymphocytes through antigen-presenting cell-T cell conjugate isolation.
Corrigendum to "Safety and Efficacy of Tumor-Infiltrating Lymphocyte Therapy with Reduced-Dose Lymphodepleting Conditioning in High-Risk Metastatic Melanoma Patients".
CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.
GAN-enhanced digital twins for biomarker-guided cancer immunotherapy and adoptive cell therapy: a mini review.
Clonally Expanded CD8 T Cells in AML Adopt an NK-Like Program Distinct from Canonical Exhaustion.
Cullin-5 RING E3 ligase limits CD8⁺ T-cell persistence and effector responses during chronic antigen stimulation.
TCR sensitivity shapes recognition of tumor antigen presented by host cells and TCR-T cell efficacy in solid tumors.
Fueling the sentinels: organelle remodeling and metabolic adaptation in tissue-resident memory T cell persistence.
Emerging immunotherapies in melanoma beyond immune checkpoint inhibitors: Vaccines, intralesional therapies, adoptive cell therapies, and T-cell engagers.
CRISPRa screen unveils noncanonical NF-κB to boost the antitumor activity of TCR-based CAR-T cells.
Discovery of Avian TCRVβ2+ T Cells Recognizing the Endogenous Ganglioside via a chCD1.1-Dependent Pathway.

Thorac Cancer. 2026 Oct;17(20): e70400

Clinicopathological Features of DLL3 Expression and T-Cell Infiltration in LCNEC: Insights From Pathology and Clinical Response to Tarlatamab.

Shotaro Kaneko, Naoki Furuya, Yoshihisa Sugiura, Hajime Tsuruoka, Kazuhiro Nishiyama, Honoka Morita, Tomoki Okura, Hisashi Saji, Junki Koike, Nobuyuki Ohike, Masamichi Mineshita.

   BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive lung neuroendocrine neoplasm with poor prognosis. Recently, DLL3-targeted bispecific T-cell engagers (BiTEs) have shown promising efficacy in small cell lung cancer, and clinical trials are ongoing in LCNEC. This study evaluated DLL3 expression and CD8+ tumor-infiltrating lymphocytes (TILs) infiltration in LCNEC and investigated their clinical significance and association with tarlatamab efficacy.
METHODS: We retrospectively reviewed consecutive patients who were diagnosed with LCNEC. Immunohistochemical analyses for DLL3 and CD8 were performed. DLL3 positivity was defined as staining in ≥ 1% of tumor cells. CD8+ TIL infiltration was graded as low, moderate, or high.
RESULTS: Among 77 screened LCNEC cases, 44 were eligible for analysis. The median age was 75 years. DLL3 expression was observed in 70.5% of cases and was associated with worse survival. Low CD8+ TIL infiltration was observed in 59.1% of cases. Patients with high CD8+ TIL infiltration demonstrated significantly longer survival than those with low infiltration (p = 0.03). Among representative clinical cases, a patient with DLL3 (+)/CD8 TILs (-) LCNEC achieved marked tumor shrinkage, whereas a patient with DLL3 (-)/CD8 TILs (-) LCNEC showed no response.
CONCLUSIONS: DLL3 is frequently expressed in LCNEC and correlates with a poorer prognosis. A majority of LCNEC cases are immunologically characterized as cold tumors lacking CD8+ TILs, which contributes to unfavorable clinical outcomes. Tarlatamab induced a robust antitumor response even in a DLL3 (+) cold tumor. DLL3-BiTE represents a promising therapeutic strategy for DLL3 (+) LCNEC.

Keywords:  CD8; DLL3; T‐cell infiltration; bispecific T‐cell engager; tarlatamab

DOI:  https://doi.org/10.1111/1759-7714.70400
Cancers (Basel). 2026 Sep 23. pii: 3085. [Epub ahead of print]18(19):

TILs in Breast Cancer: Paving New Ways Beyond Their Prognostic and Predictive Values.

Jean-Marc Ferrero, Loïc Trapani, Rym Bouriga, Baharia Mograbi, Jocelyn Gal, Gérard Milano.

  Tumor-infiltrating lymphocytes (TILs) measurement has emerged as a critical biomarker in breast cancer management, being considered as having strong prognostic and predictive values, particularly in triple-negative cases where the clinical interest of TILs determination is clearly established. The central aim of this viewpoint article is to delineate interesting new avenues for enlarging TILs' clinical usefulness in breast cancer. First, the advent of computational methods, including artificial intelligence (AI), represents a major shift toward improving TILs assessment, potentially reducing inter-observer variability and enabling reproducible scoring across institutions. Secondly, integrating emerging immunological tumoral markers like TLS (tertiary lymphoid structures) and CRATERs (CD8+ T cell structures) with TILs could further improve treatment outcome prediction. Thirdly, TIL levels may be modulated through the optimized use of chemotherapy, anti-angiogenic agents, and cancer vaccines. More knowledge continues to be gained regarding factors influencing TIL levels, including parity and breastfeeding, exposure to infection, metabolic stress, and environmental factors that contribute to immune fitness across the lifespan.

Keywords:  artificial intelligence; breast cancer; predictive markers; prognostic markers; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers18193085
Clin Breast Cancer. 2026 Sep 17. pii: S1526-8209(26)00170-9. [Epub ahead of print]26(11): 17-24

Value of Breast and Axillary Tumor-Infiltrating Lymphocytes for Response to Neoadjuvant Chemo-(Immuno)Therapy in Clinically Node-Positive Breast Cancer.

REFINE study group

   INTRODUCTION: Accurate prediction of pathologic complete response (pCR) after neoadjuvant chemo-(immuno)therapy (NAC) is clinically relevant in clinically node-positive (cN+) breast cancer patients. This study evaluated the association of pre-NAC tumor-infiltrating lymphocytes (TILs) in the breast tumor and axillary lymph node metastases (ALNMs) with breast, axillary, and combined pCR. Second, correlations between pre-NAC breast tumor and ALNM TILs, and between pre- and post-NAC breast tumor TILs were analyzed.
METHODS: This retrospective study included cN+ breast cancer patients treated with NAC from the prospective multicenter RISAS trial (NCT02800317). Pre-NAC breast tumor and ALNM TILs and post-NAC breast tumor TILs were centrally assessed and classified as low (< 10%), intermediate (10%-40%), or high (> 40%). Logistic regression, receiver operating characteristic curve, and Spearman's rank correlation analyses were performed.
RESULTS: Of 206 included patients, 29.6% (61/206) achieved breast pCR, 31.1% (64/206) axillary pCR and 23.3% (48/206) combined pCR. Increased breast tumor TILs were associated with stepwise higher breast (21.4%, 30.4%, 53.1%; P = .004), and axillary (25.0%, 30.4%, 53.1%; P = .014) pCR rates for low, intermediate, and high TIL levels. ALNM TILs were not associated with any pCR. Weak-to-moderate positive correlations were found between pre-NAC breast tumor and ALNM TILs (rs = 0.36, P = .001) and pre- and post-NAC breast tumor TILs (rs = 0.47, P < .001).
CONCLUSION: Pre-NAC breast tumor TILs were associated with breast and axillary pCR, whereas ALNM TILs were not predictive of any pCR in cN+ breast cancer patients treated with NAC. Weak-to-moderate positive correlations were found between pre-NAC breast tumor and ALNM TILs and pre- and post-NAC breast tumor TILs.

Keywords:  Breast neoplasms; Immune response; Lymph nodes; Neoadjuvant therapy; Pathologic complete response

DOI:  https://doi.org/10.1016/j.clbc.2026.09.007
Transl Cancer Res. 2026 Sep 30. 15(9): 717

Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review.

Nannan Ma, Chunxiang Shang.

   Background and Objective: Lung cancer remains a leading cause of cancer-related mortality. Cellular immunotherapy has achieved major advances in hematologic malignancies, but translation to lung cancer is constrained by antigen heterogeneity, limited trafficking and persistence, an immunosuppressive tumor microenvironment (TME), manufacturing complexity, and on-target off-tumor toxicity. This narrative review summarizes current clinical evidence, major translational barriers, and future development strategies for cellular immunotherapy in lung cancer.
Methods: PubMed, Web of Science, Embase, and ClinicalTrials.gov were searched from database inception to 1 June 2026 using Medical Subject Headings (MeSH) and free-text terms. Evidence on chimeric antigen receptor T-cell (CAR-T), T-cell receptor-engineered T-cell (TCR-T), tumor-infiltrating lymphocyte (TIL), natural killer (NK), chimeric antigen receptor natural killer (CAR-NK), and cancer vaccine-based strategies was reviewed, with priority given to non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).
Key Content and Findings: Most lung-cancer cellular therapy studies remain early phase. TIL therapy has demonstrated clinical activity in NSCLC, while EGFR, MSLN, CEA, MUC1, PD-L1, B7-H3, and DLL3 are representative targets under investigation for CAR-based approaches; NY-ESO-1 and KK-LC-1 are representative TCR-T targets. Major barriers include antigen escape, poor tumor infiltration, HLA restriction or loss, immunosuppressive signaling, cellular exhaustion, limited persistence, manufacturing burden, and treatment-related toxicity. Current optimization strategies include gene editing, chemokine-receptor engineering, armored or logic-gated receptors, safety switches, optimized lymphodepletion, and rational combinations with other anticancer therapies.
Conclusions: Cellular immunotherapy is a promising but still developing strategy for lung cancer. Future studies should prioritize biomarker-guided patient selection, safer and more persistent cell products, scalable manufacturing, and prospective clinical validation of rational combination strategies.

Keywords:  Lung cancer; cellular immunotherapy; chimeric antigen receptor T-cell therapy (CAR-T therapy); tumor microenvironment (TME); tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.21037/tcr-2026-1627
Cancers (Basel). 2026 Sep 23. pii: 3087. [Epub ahead of print]18(19):

Evaluation of MRI Radiomic Features as Surrogates of Tumor Immune Status in Breast Cancer: A Pilot Study of MRI-Derived Radiomic Features for Non-Invasive Immune Profiling in Breast Cancer.

Mimansha Shah, Soaham Kumar, Narendra Kumar, Jayshree Mishra.

   BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and CD8+ T cell density are important predictors of immunotherapy response in breast cancer, but their evaluation requires invasive tissue biopsies. Radiomics, which enables high-throughput extraction of quantitative imaging features, offers a promising non-invasive approach to characterize the tumor immune microenvironment (TIME). This study evaluates whether MRI-derived radiomic features could predict immune infiltration status in breast cancer. Additionally, we have developed an on-line browser-based tool that can predict the immune status of the tumor environment.
METHODS: Preoperative MRI and matched transcriptomic data from 38 breast cancer patients were obtained from TCIA and TCGA-BRCA datasets. Tumors were manually segmented using 3D Slicer, and radiomic features were extracted using PyRadiomics. Eighteen biologically relevant radiomic features associated with immune status were selected for modeling. Immune markers included CD8B gene expression, CD8+ T cell infiltration estimated by CIBERSORT, and Immune Score estimated by ESTIMATE. Machine learning models, including Random Forest, Support Vector Machine, Deep Learning, and Elastic Net, were trained to classify immune-high versus immune-low tumors, followed by validation in an independent cohort of 13 patients.
RESULTS: Random Forest demonstrated strong internal performance (AUCs of 0.945, 0.993, and 0.974 for CD8B expression, CD8+ T cell infiltration, and Immune Score, respectively), but this dropped substantially in the held-out test partition and in an independent external validation cohort (n = 13, AUC 0.44-0.64), indicating that the internal metrics likely reflect overfitting at this sample size and should not be interpreted as evidence of generalizable performance. Additionally, we developed RadioImmune, a browser-based prototype research/demo tool that uses a logistic-regression approximation (not the Random Forest model above) for exploratory, real-time estimation of total immune score and CD8+ T cell infiltration status from radiomic inputs; its performance is not represented by the Random Forest AUCs reported above.
CONCLUSIONS: These findings provide proof-of-concept that MRI-based radiomic features may serve as potential non-invasive biomarkers of the breast tumor immune microenvironment, pending validation in larger, independent cohorts.

Keywords:  CD8+ T cells; CIBERSORT; PyRadiomics; breast cancer; immune score; immunotherapy biomarker; machine learning; radiomics; tumor immune microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers18193087
Front Immunol. 2026 ;17 1936815

Clinical trial landscape and translational priorities for adoptive T-cell and NK-cell therapies in gynecologic malignancies.

Qingyu Chen, Yuxin Zhu, Shilin Ye, Yaoyi Wang, Huilong Lin.

   Background: Adoptive T-cell and natural killer (NK)-cell therapies are expanding across solid tumors, but their registered development in gynecologic malignancies remains difficult to interpret because many studies use basket designs and registry records vary in detail.
Methods: We conducted a cross-sectional analysis of therapeutic adoptive T-cell and NK-cell trial records identified from TrialTrove, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. Trials were classified into three mutually exclusive evidence-specificity groups: single gynecologic disease family specific, multiple gynecologic disease families only, and broader baskets including non-gynecologic cancers. We evaluated source sensitivity, target applicability, field-specific registry visibility, and the availability of posted registry safety results. A complementary registry-informed exploratory survey of 25 experts assessed translational barriers and development priorities using domain-specific 1-5 scales.
Results: Among 442 unique records screened, 211 therapeutic trials met the eligibility criteria. Of these, 43 were restricted to a single gynecologic disease family, 2 included multiple gynecologic disease families only, and 166 were broader basket trials permitting enrollment of non-gynecologic malignancies. The public-registry-linked and public-search-captured sensitivity subsets included 200 and 141 records, respectively, with broadly similar structural patterns across datasets. The landscape was predominantly early phase, with 149 Phase I and 50 Phase I/II trials. CAR-T, TIL, and TCR-T were the leading modalities, accounting for 79, 60, and 42 trials, respectively. Only 20 records had posted registry results with an adverse-event module, indicating limited availability of registry-reported safety data. In the exploratory expert survey, an immunosuppressive tumor microenvironment and a lack of gynecologic-specific cohorts were identified as leading barriers, whereas ovarian cancer, TIL therapy, MSLN, target reporting, and registry completeness emerged as prominent development priorities.
Conclusions: Registered cellular-therapy activity in gynecologic malignancies is broad but remains early phase, largely basket-derived, and unevenly visible in registry fields. Separating disease-specific trials from broader eligibility-only baskets, testing source sensitivity, and distinguishing modality biology from missing target reporting provide a more reproducible basis for future trial planning.

Keywords:  CAR-T; TCR-T; adoptive cellular therapy; clinical trials; gynecologic malignancies; natural killer cells; registry-based landscape; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1936815
Mol Biol Rep. 2026 Oct 12. pii: 1718. [Epub ahead of print]53(1):

Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives.

Gulnihol Sharipova, Shavkat Amonov, Antonina Kim, Sardor Kenjayev, Nasiba Masharipova, Zoxidxo'ja Maxkamov, Shakhimardan Shaniyazov, Zebiniso Alimova.

  Oral cavity tumors remain a major global health challenge, with poor outcomes in patients with locally advanced, recurrent, or metastatic disease despite advances in surgery, radiotherapy, chemotherapy, and targeted therapies. Immunotherapy has emerged as a potential strategy to restore antitumor immunity and overcome tumor-induced immune suppression. This narrative review synthesizes recent advances in immunotherapy for oral cavity tumors, focusing on immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitor (TKI) antibodies, near-infrared photoimmunotherapy (NIR-PIT), bispecific antibodies (BsAbs), oncolytic viruses (OVs), cytokine therapies, and adoptive cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR)-T/natural killer (NK), and T cell receptor (TCR)-T therapy. The review also examines the pivotal role of the immunosuppressive tumor microenvironment (TME) in shaping treatment response and therapeutic resistance, highlighting the contributions of regulatory immune cells, cancer-associated fibroblasts (CAFs), hypoxia, extracellular matrix (ECM) remodeling, and immune exclusion. Current clinical evidence demonstrates meaningful survival benefits with programmed cell death protein 1 (PD-1) inhibitors in recurrent/metastatic disease and expanding opportunities for perioperative immunotherapy, while numerous emerging modalities remain under active clinical investigation. However, durable responses remain limited by tumor heterogeneity, inadequate immune cell trafficking, antigen escape, manufacturing challenges, and the lack of reliable predictive biomarkers. Future progress will likely depend on biomarker-guided patient selection, rational combination strategies, and engineered cellular therapies that can overcome microenvironment-mediated resistance. Collectively, these findings support continued investigation of personalized, multimodal immunotherapy as a viable avenue for improving outcomes in patients with oral squamous cell carcinoma (OSCC).

Keywords:  Cell therapy; Immune checkpoint inhibitors; Immunotherapy; Oncolytic virus therapy; Oral squamous cell carcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11033-026-12906-4
J Immunol. 2026 Oct 01. pii: vkag187. [Epub ahead of print]215(10):

CRISPR-Cas9 screen identifies eIF4G2 as a regulator of CD8+ T cell dysfunction.

Erin A Holcomb, Long Jiang, Ashley N Pearson, Jadyn James, Akshay Tate, Zhuwen Wang, Anwesha Dasgupta, Jim Clauwaert, Nicholas D Armas, Ameer L Elaimy, Dilrukshika S W Palagama, Samantha K Goodwin, Matthew J Kwiatkowski, Miguel Gijón, Meredith A Morgan, Adam H Courtney, Shannon A Carty, Amanda K Huber, Weiping Zou, John R Prensner, Michael D Green.

  CD8+ T cells directly target and kill cancer cells and are required for effective antitumor immunity. However, CD8+ T cells may become dysfunctional when exposed to chronic antigen stimulation during cancer. Dysfunction is characterized by reduced proliferation, increased expression of inhibitory receptors, and impaired effector function, yet the genetic mechanisms controlling dysfunction remain poorly understood. Therefore, we developed a murine ex vivo chronic stimulation model that recapitulates features of CD8+ T cell dysfunction observed within the tumor microenvironment. By coupling this system with genome-wide CRISPR-Cas9 loss-of-function screening, we discovered that the progression of murine CD8+ T cells to a dysfunctional state required eIF4G2, a noncanonical mRNA translation factor. Deletion of eIF4G2 restored CD8+ T cell survival and proliferation during chronic stimulation conditions in vitro. Transcriptomic, proteomic, and flow cytometric analyses revealed that eIF4G2 deletion shifts CD8+ T cell phenotype from a dysfunctional state to a proliferative state. eIF4G2 depletion reduced oxidative stress, lipid peroxidation, and accumulation of misfolded protein aggresomes during chronic in vitro stimulation. Finally, eIF4G2-depleted cells mediated enhanced tumor control in a murine model of melanoma. These data suggest that targeting eIF4G2 may promote CD8+ T cell resilience and improve therapeutic antitumor immunity.

Keywords:  T cell; adoptive cell therapy; immunotherapy; tumor microenvironment; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1093/jimmun/vkag187
J Immunother Cancer. 2026 Oct 15. pii: e014996. [Epub ahead of print]14(10):

Selective expansion of neoantigen-specific peripheral blood lymphocytes through antigen-presenting cell-T cell conjugate isolation.

Mamduh Khateb, Raina Jung, Patrick Hadley, Stav Leibou, Zhiya Yu, Aaron J Dinerman, Victoria Dulemba, Billel Gasmi, Noam Levin, Sanghyun Peter Kim, Aarushi Bhasin, Deepali Bhat, Sivasish Sindiri, Jared J Gartner, Todd D Prickett, Tiffany Benzine, Shahram Farid, Maria Parkhurst, Hyunmi Halas, Guangzhe Ge, Yaqiang Cao, Keji Zhao, James C Yang, Paul Robbins, Frank J Lowery, Sri Krishna, Theo Heller, Daniel Mcvicar, Steven A Rosenberg, Nicholas D Klemen.



Keywords:  Adoptive cell therapy - ACT; Gastrointestinal Cancer; Immunotherapy; T cell

DOI:  https://doi.org/10.1136/jitc-2026-014996
Transplant Cell Ther. 2026 Oct 14. pii: S2666-6367(26)00763-3. [Epub ahead of print]

Corrigendum to "Safety and Efficacy of Tumor-Infiltrating Lymphocyte Therapy with Reduced-Dose Lymphodepleting Conditioning in High-Risk Metastatic Melanoma Patients".

Lilit Karapetyan, Joel Kuriakose, Elizabeth DiMaggio, Kimberly Ward, Jamie Chau, Christopher Otteni, Denise Kalos, Johannes Ali, MacLean S Hall, Matthew Beatty, Olga V Klinkova, Mohammed E Alomar, Eric E Gaskill, Rebecca M Gonzalez, Hanna Bailey, Michael Yu, Nam Tran, Lianicet Rodriguez-Alfonso, Ella Vieira, Karla Adams, Michael Jain, Frederick L Locke, Jobelle Baldonado, Matthew C Perez, John Mullinax, Jonathan S Zager, Ricardo Gonzalez, Vernon K Sondak, Joseph Markowitz, Andrew S Brohl, Zeynep Eroglu, Ahmad A Tarhini, Nikhil I Khushalani, James J Mulé, Amod A Sarnaik, Shari Pilon-Thomas.

DOI: https://doi.org/10.1016/j.jtct.2026.09.032
Mol Biomed. 2026 Oct 10. pii: 201. [Epub ahead of print]7(1):

CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.

Lylou Milian, Mannon Geindreau, Cassandre Pignol, Frédérique Vegran.

  The infiltration of tumors by CD8⁺ T lymphocytes is a critical determinant of antitumor immunity and response to immunotherapy. However, the presence of tumor-specific CD8⁺ T cells does not necessarily translate into effective tumor control, as multiple biological barriers can prevent their recruitment, spatial distribution, persistence, and functional activity. This review provides a comprehensive overview of the multistep mechanisms regulating CD8⁺ T-cell infiltration, from immune priming and systemic trafficking to vascular entry, intratumoral migration, and tissue residency. We discuss how alterations in chemokine networks, dysfunctional tumor vasculature, extracellular matrix remodeling, stromal barriers, and immunosuppressive signals collectively drive immune exclusion and resistance to therapy. Unlike previous reviews that have focused on individual aspects of T-cell trafficking, tumor immune contexture, or immune exclusion, we integrate these interconnected mechanisms as successive biological checkpoints and link them to therapeutic strategies aimed at overcoming specific barriers. These include restoration of antigen presentation and dendritic cell function, reprogramming of chemokine pathways, vascular normalization, stromal remodeling, innate immune activation, and induction of tertiary lymphoid structures. This integrated framework highlights why increasing CD8⁺ T-cell infiltration alone may be insufficient and supports the development of rational, sequential, and spatially guided combination strategies. Advances in spatial transcriptomics, single-cell technologies, and multiplex imaging are expected to enable personalized identification of dominant immune barriers and rational design of combination therapies. Ultimately, the goal is shifting from simply activating T cells toward engineering tumor ecosystems that support sustained CD8⁺ T-cell infiltration, organization, and effector function.

Keywords:  CD8+ T cells; Chemokines and chemokine receptors; T cell recruitment; Tumor Microenvironment; Tumor infiltration

DOI:  https://doi.org/10.1186/s43556-026-00612-3
Front Med (Lausanne). 2026 ;13 1894314

GAN-enhanced digital twins for biomarker-guided cancer immunotherapy and adoptive cell therapy: a mini review.

Jiayu Yang.

  Cancer immunotherapy and adoptive cell therapy have transformed modern oncology, yet durable benefits remain limited by tumor heterogeneity, immune escape mechanisms, biomarker variability, and the dynamic remodeling of the tumor immune microenvironment. Current biomarker strategies, including PD-L1 (programmed death-ligand 1) expression, microsatellite instability (MSI), tumor mutational burden (TMB), immune gene signatures, liquid biopsy measurements, and target antigen profiles, provide clinically useful information but are often static and insufficient to capture longitudinal tumor-immune-therapy interactions. Digital twin technology offers a computational paradigm for integrating multi-omics, immune profiling, clinical variables, imaging, and treatment-response data into patient-linked virtual models. Generative artificial intelligence, including generative adversarial networks (GANs), may enrich sparse biomarker-defined state spaces and support the simulation of underrepresented treatment response or toxicity trajectories. This mini review critically compares mechanistic quantitative systems pharmacology, spatial and agent-based modeling, data-driven prediction, and emerging digital twin approaches and proposes a platform-agnostic architecture that can be implemented in MATLAB/Simulink or other computational environments. The adoptive cell therapy scope focuses on chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor natural killer cell (CAR-NK), and T-cell receptor-engineered T-cell (TCR-T) therapies, with related principles applicable to tumor-infiltrating lymphocyte (TIL) therapy. We describe conditional and longitudinal GAN strategies, dynamic tumor-immune state modeling, biomarker integration, validation metrics, governance, and prospective implementation pathways. The proposed framework is conceptual and has not yet been clinically validated; synthetic data are treated as methodological support rather than clinical evidence. Its intended near-term uses are hypothesis generation, virtual-cohort enrichment, trial design, and uncertainty-aware decision support.

Keywords:  adoptive cell therapy; cancer immunotherapy; digital twin; generative adversarial network; multimodal biomarkers; precision oncology; quantitative systems pharmacology

DOI:  https://doi.org/10.3389/fmed.2026.1894314
bioRxiv. 2026 Oct 01. pii: 2026.09.30.755147. [Epub ahead of print]

Clonally Expanded CD8 T Cells in AML Adopt an NK-Like Program Distinct from Canonical Exhaustion.

Yunli E Chu, Matthew A Cottam, Chad R Potts, Thomas Gracie, Ciarra Polsley, Justin A Cartailler, Michael R Savona, Rui Lu, Stanley C Lee, Robert Welner, P Brent Ferrell.

CD8 T cells are key mediators of anti-tumor immunity, yet their differentiation states and clonal architecture within the acute myeloid leukemia (AML) bone marrow microenvironment remain incompletely defined. We performed high dimensional immune profiling of bone marrow samples from 46 newly diagnosed AML patients using mass cytometry to probe the microenvironment and T cell states. We used single-cell RNA and T cell receptor (TCR) sequencing to define CD8 T cell phenotypes, transcriptional states, and clonal architecture. AML-associated CD8 T cells were skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), while canonically exhausted T cell populations were rare. Functional studies revealed that TEMRA CD8 T cells robustly produced IFNγ and TNFα upon in vitro stimulation. Clonal expansion was concentrated within the TEMRA compartment. Comparison of TCR sequences with known viral epitopes identified a small subset of expanded viral-specific clonotypes, while the majority of highly expanded clonotypes had unknown specificity and may include AML-specific T cells. Differential gene expression analysis revealed shared cytotoxic effector programs during clonal expansion but diverging activation signatures: viral-specific clones upregulated canonical T cell receptor signaling genes, whereas expanded clones of unknown specificity exhibited enrichment of natural killer (NK) receptor-associated genes. These genes comprised the leukemia-associated NK-immune (LaNKi) score which was elevated in an independent AML dataset compared to pan cancer tumor infiltrating lymphocytes. These findings define the CD8 T cell differentiation landscape and clonal architecture in AML marrow at diagnosis and suggest that T cell dysfunction in AML diverges from classical activation and exhaustion paradigms.
Key points: CD8 T cells in AML are enriched for terminally differentiated states not defined by traditional checkpoint-inhibitor expression.The LaNKi score marks clonally expanded CD8 T cells of unknown specificity and is validated across independent AML and pan-cancer datasets.

DOI: https://doi.org/10.64898/2026.09.30.755147
Cancer Immunol Res. 2026 Oct 15.

Cullin-5 RING E3 ligase limits CD8⁺ T-cell persistence and effector responses during chronic antigen stimulation.

Justin D Saco, Daniel Karin, J J Patten, Stefanie Bachl, Carter Ching, Nupura Kale, Yichen Fan, Egmidio Medina, Nataly Naser Al Deen, Ameya Champhekar, William G Kaelin, Brenda A Schulman, Katie M Campbell, Julia Carnevale, Cristina Puig-Saus, Antoni Ribas.

T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8⁺ T cells expressing an NY-ESO-1-specific T-cell receptor and subjected them to repeated tumor cell rechallenge. These screens revealed enrichment of single-guide RNAs targeting components of Cullin-RING E3 ligases, particularly Cullin-5 (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0181
Cancer Immunol Res. 2026 Oct 12.

TCR sensitivity shapes recognition of tumor antigen presented by host cells and TCR-T cell efficacy in solid tumors.

Mete Can Odabasi, Thomas Kammertoens, Elfriede Nößner, Kordelia Hummel, Matthias Richter, Anje Sporbert, Manuel Wagner, Wolfgang Uckert, Thomas Blankenstein, Matthias Leisegang.

Despite advances in adoptive T cell therapy, therapeutic efficacy in solid tumors remains inconsistent, and the mechanistic determinants of treatment failure are incompletely understood. Increasing evidence suggests that effective antitumor responses depend not only on direct recognition of malignant cells but also on interactions with the tumor microenvironment, including non-malignant host cells that cross-present tumor antigens. Using an HLA-A2-transgenic syngeneic mouse cancer model that enables near-physiological presentation of human tumor antigens by both malignant and host cells, we investigated how TCR antigen sensitivity relates to therapeutic outcome. We compared T cell receptor-engineered (TCR-)T cells with different antigen sensitivities directed against the same HLA-A2-restricted melanoma antigen. Although high- and low-sensitivity TCR-T cells recognized tumor cells comparably in vitro, only high-sensitivity TCR-T cells mediated durable tumor regression in vivo. Improved tumor control correlated with enhanced recognition of cross-presented tumor antigen on tumor-associated CD11b+ myeloid cells and increased intratumoral effector activity. IFN-γ levels in tumor tissue and peripheral blood reflected intratumoral T cell activity and correlated with therapeutic response. Together, these findings identify host cell antigen recognition as a sensitivity-dependent functional correlate of TCR-T cell efficacy and provide a mechanistic explanation for the superior activity of higher-sensitivity TCRs in solid tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0367
Front Immunol. 2026 ;17 1969351

Fueling the sentinels: organelle remodeling and metabolic adaptation in tissue-resident memory T cell persistence.

Ziheng Zheng, Xuechun Yang, Minqian Ou, Yuedong Chen, Deyong Gan.

  Tissue-resident memory T (TRM) cells persist at barrier and parenchymal sites where oxygen, nutrients, and inflammatory signals fluctuate. Their durability therefore cannot be explained by tissue retention alone. Evidence from skin, liver, intestine, lung, tumors, and inflamed tissues supports a coupled program in which local nutrient capture, mitochondrial fuel selection, organelle dynamics, autophagy, mitophagy, and proteostatic responses sustain survival while preserving rapid effector competence. We propose "organelle-niche matching" as a testable four-step working model: tissue inputs engage nutrient-, oxygen-, danger-, cytokine-, and antigen-sensing pathways; these regulate mitochondrial biogenesis, fusion-fission balance, respiratory-chain organization, and selective turnover; organelle state controls bioenergetic reserve, redox balance, apoptosis, and metabolite availability; and these outputs may reinforce or destabilize transcriptional residency and recall. The model integrates evidence across contexts, not one pathway established in a single TRM population. Direct TRM evidence is distinguished from tumor-infiltrating lymphocyte data and extrapolation from conventional memory CD8+ T cells. Lipid uptake and fatty-acid oxidation are prominent in selected TRM niches but are not universal, and mitophagy should not be equated with mitochondrial health. This framework identifies causal links already demonstrated in TRM cells, relationships that remain correlative, and therapeutic opportunities to strengthen protective residents without sustaining pathogenic populations.

Keywords:  autophagy; fatty-acid oxidation; immunometabolism; mitochondria; mitophagy; persistence; tissue niche; tissue-resident memory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1969351
Cancer Treat Res Commun. 2026 Oct 14. pii: S2468-2942(26)00391-6. [Epub ahead of print]49 101482

Emerging immunotherapies in melanoma beyond immune checkpoint inhibitors: Vaccines, intralesional therapies, adoptive cell therapies, and T-cell engagers.

Ida Taglialatela, Leonardo Di Corcia, Andrea Boutros, Alice Gatti, Andrea Sponghini, Elia Esposto, Pamela Farinelli, Roberto Giorgione, Francesca Zottarelli, Elisa Zavattaro, Paola Savoia, Alessandra Gennari.

   BACKGROUND: Immune checkpoint inhibitors have transformed the management of melanoma, yet many patients do not achieve durable benefit. Novel immunotherapeutic strategies are being developed in both cutaneous and uveal melanoma.
METHODS: This narrative review summarizes four classes of emerging immunotherapies: personalized cancer vaccines, intralesional immunotherapies, adoptive cell therapies, and bispecific T-cell engagers, focusing on mechanisms of action, clinical trial outcomes, limitations, and evidence maturity.
RESULTS: In the randomized phase IIb KEYNOTE-942 trial, adding the individualized mRNA vaccine mRNA-4157/V940 to adjuvant pembrolizumab prolonged recurrence-free survival (RFS; hazard ratio [HR] 0.561, 95% confidence interval [CI] 0.309-1.017), a hypothesis-generating result under phase III evaluation. In the phase III PIVOTAL trial, neoadjuvant intralesional daromun improved RFS compared with upfront surgery in resectable, mostly recurrent stage III melanoma (HR 0.55, 95% CI 0.38-0.78). The tumor-infiltrating lymphocyte therapy lifileucel and the oncolytic virus RP1 plus nivolumab received accelerated approval for anti-PD-1-refractory melanoma based on single-arm studies (objective response rates approximately 31-33%, with durable responses). In human leukocyte antigen HLA-A*02:01-positive metastatic uveal melanoma, the T-cell engager tebentafusp improved overall survival (OS) in a phase III trial. Preferentially expressed antigen in melanoma (PRAME)-directed T-cell receptor (TCR)-engineered T cells and T-cell engagers have shown activity in early-phase studies.
CONCLUSIONS: These approaches expand therapeutic options for melanoma, but randomized evidence of improved outcomes is available only for some. HLA restriction, treatment burden, and manufacturing complexity remain key challenges, and ongoing phase III trials will define their clinical role.

Keywords:  Adoptive cell therapy; Cancer vaccine; Intralesional immunotherapy; Melanoma; T-cell engager

DOI:  https://doi.org/10.1016/j.ctarc.2026.101482
Cell Mol Immunol. 2026 Oct 13.

CRISPRa screen unveils noncanonical NF-κB to boost the antitumor activity of TCR-based CAR-T cells.

Hanyang Yu, Yingxin Wu, Yue Liu, Ruxue Wei, Zhixiao Zhou, Li Yu, Xin Lin, Jiasheng Wang.

  Engineering autologous T cells for adoptive therapies has revolutionized cancer treatment, yet limited persistence remains a major barrier to robust clinical responses and durable disease control. Although costimulation with 4-1BB markedly improves CAR-T-cell persistence, no comparably effective approach has been identified to enhance persistence in T-cell therapies that rely on native TCR signaling, including conventional TCR-T cells and synthetic T-cell receptor and antigen receptor (STAR) T cells. To identify intrinsic persistence regulators in a TCR-based context, we performed an in vivo CRISPR activation screen in STAR-T cells and identified the noncanonical NF-κB axis, with RELB as the top hit. Direct RELB overexpression, however, exhibited dose-dependent cytotoxicity, motivating a translational alternative: overexpression of p52, the ncNF-κB transcription partner of RELB. Under prolonged antigen exposure, p52 overexpression sustained proliferation, preserved effector functions, and increased the intratumoral trafficking potential, particularly in CD8⁺ T cells, thereby yielding superior tumor control. Mechanistically, transcriptomic profiling revealed coordinated upregulation of cell cycle programs and chemokine receptors, along with downregulation of apoptosis and exhaustion-associated modules. Moreover, p52 overexpression restored RELB nuclear translocation in the context of PD-1/PD-L1 engagement, indicating partial resistance to checkpoint-mediated suppression and sustained ncNF-κB activity in PD-L1hi immunosuppressive environments. Collectively, our findings identify p52 as an antigen-dependent enhancer of ncNF-κB, conferring durable persistence and checkpoint resilience on TCR-based T cells and providing a feasible strategy to improve therapeutic effects in solid tumors.

Keywords:  CRISPR activation screening; Non-canonical NF-κB signaling; STAR; T cell persistence; p52

DOI:  https://doi.org/10.1038/s41423-026-01471-2
Eur J Immunol. 2026 Oct;56(10): e70302

Discovery of Avian TCRVβ2+ T Cells Recognizing the Endogenous Ganglioside via a chCD1.1-Dependent Pathway.

Nitin Kamble, Faisal R Anjum, Shahriar Behboudi.

  This study presents the discovery and first functional characterization of chicken lipid-reactive Natural Killer T (NKT)-like cells, resolving a long-standing knowledge gap in avian immunology. Using purified TCRVβ2+ lymphocytes, we demonstrate through rigorous experiments combining shRNA-mediated gene silencing, pharmacological pathway blockade, primary MACS-purified co-cultures, and intracellular cytokine flow cytometry that these cells are activated by CpG-ODN-stimulated antigen-presenting cells (APCs). Activation selectively depends on APC-driven glycosphingolipid (GSL) biosynthesis, with CpG-ODN significantly upregulating key biosynthetic enzymes (ST3GAL1 and ST3GAL5) in APCs. Silencing of enzymes involved in this pathway or chemical inhibition of GSL synthesis abrogated T cell activation. We identify GM3 as a potent, functional lipid ligand activating TCRVβ2+ lymphocytes. In parallel, IL-12 and IL-18 trigger IFN-γ production from TCRVβ2+ lymphocytes, crucially requiring live APC interactions. Upon activation of splenocytes with GM3, the cells expressed chIL-2, chIL-4, chIL-17, Granzyme A, and Perforin. By establishing functional, nonpeptide lipid-reactive T cells in chickens, these findings redefine the conceptual framework of avian innate-like T cell immunology. This discovery unlocks a highly translatable, universal target for lipid-adjuvanted poultry vaccines to enhance global animal health and food security.

Keywords:  CD1.1; NKT cells; T cells; TCR; gangliosides

DOI:  https://doi.org/10.1002/eji.70302