bims-tuinly 2026-10-25 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–10–25
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Platform-based manufacturing of tumor-infiltrating lymphocytes derived from different solid tumor types.
BCL2A1 marks an early, less-exhausted CD8+ tumor-infiltrating lymphocyte state associated with PD-1 blockade response in NSCLC.
Comparative analysis of ovarian cancer tumor-infiltrating T cells with those in melanoma and before and after PD-1 blockade.
Innovations and emerging trends in adoptive cell therapies for solid tumors: engineering strategies and clinical translation.
Stromal tumor-infiltrating lymphocytes (sTIL) in laryngeal squamous cell carcinoma: association with pharyngocutaneous fistula, recurrence, and mortality.
Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy.
Predicting Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer Using Machine Learning of MRI Radiomics.
HPV16 E7-Containing Exosomes May Contribute to PD-L1 Expression in Tumor-Infiltrating Lymphocytes of Cervical Cancer.
Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors.
A multimodal deep learning radiomics nomogram integrating clinicopathological features for predicting pathological complete response after neoadjuvant therapy in triple-negative breast cancer: a multicenter retrospective study.
Systemic antitumor responses to hypofractionated radiotherapy plus Poly(I:C) in advanced hepatocellular carcinoma: A phase 2 trial.
Stromal B7-H3 Expression Characterizes an Immune-Hot Microenvironment and Predicts Response to PD-1 Blockade in Gastric Cancer.
Lung neuroendocrine cancer induces immunosuppressive macrophages via serotonin to drive resistance to the T cell engager tarlatamab.
State-Dependent Decoupling of a CREM-Centric cAMP-Responsive Regulon and Survival in Hepatocellular Carcinoma.
T Cell Receptor-Engineered T Cell Therapy in Solid Tumors: Where We Stand and What's to Come.
Fenofibrate enhances systemic antitumor efficacy of high- and low-dose radiotherapy plus PD-1 blockade through CD8+ T-cell metabolic reprogramming and LDRT tumor conditioning.
Parity, breastfeeding, and reproductive timing are associated with tumour-infiltrating lymphocytes in hormone receptor-negative breast cancer: a population-based cohort study.
Radiotherapy Reprograms CCR8⁺ Regulatory T Cells via REL-NF-κB to Enforce Spatial Immune Exclusion in Hepatocellular Carcinoma.
Cellular immunotherapy for acute myeloid leukemia: from bench to bedside.
A modular synthetic promoter toolkit for programmable gene control in activated and chronically stimulated T cells.
Pimozide enhances antigen cross-presentation and promotes cytotoxic CD8+ T cell immunity by stimulating dendritic cells.
Nanomaterials Reshaping Tumor Metabolism: A New Frontier to Overcome T Cell Exhaustion.
Proteomic atlas of T cell exhaustion defines proteostatic collapse.
Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity.
ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors.
Clonal expansion of CD8+ effector T cells in patients with calcific aortic valve disease.
Tumor endothelial cells as vascular immune gatekeepers: reprogramming the vascular-immune interface for cancer immunotherapy.

Front Immunol. 2026 ;17 1854761

Platform-based manufacturing of tumor-infiltrating lymphocytes derived from different solid tumor types.

Justin Lievense, Liselotte Tas, Maaike van Zon, Kari-Anne Legué-van Duinen, Rosa van Amerongen, Sander Kouwen, Rosalie van Riessen, Femke Sluiter, Jeltsje Hagg, Madelon Badoux, Iris Manders, Eva Vedder, Erica Sellink, Tom Seijkens, Koen Hartemink, Marcus Rijken, Oscar Brouwer, Suzanne Castenmiller, Marten Hansen, Monika Wolkers, John Haanen, Jos Beijnen, Cynthia Nijenhuis, Inge Jedema, Bastiaan Nuijen.

   Background: In adoptive cell therapy with tumor-infiltrating lymphocytes (TILs), TILs are isolated and expanded ex vivo from an autologous tumor lesion. TIL therapy, comprising preparative lymphodepleting chemotherapy, TIL infusion, and post-infusion supportive interleukin-2 (IL-2) administration, has demonstrated efficacy in patients with metastatic melanoma. Interest in extending TIL therapy to other solid tumors is growing, and a tumor-agnostic manufacturing platform would allow first-in-human trials to be launched rapidly in these indications.
Objective: This study investigated whether a manufacturing process and control strategy developed for metastatic melanoma-derived TILs could be adapted into a tumor-agnostic platform for the generation of TILs from different solid tumor types, referred to as NTU101.
Methods: The feasibility of generating TILs from endometrial carcinoma (ENDC, n=9), non-small cell lung cancer (NSCLC, n=9), and penile cancer (PENC, n=10) lesions was assessed during process development (PD) runs using predefined quality criteria. Throughout PD runs, flow cytometry was used to characterize cells. When available, autologous tumor digest was used to assess the tumor-reactive potential of TILs. Based on PD experience, adjusted quality criteria were applied to manufacture one full-scale GMP NTU101-drug product (DP) per tumor type.
Results: Overall, 89% (n=25/28) of PD NTU101-DPs manufactured met the predefined quality criteria, containing at least 0.5×10^9 and 90% viable CD45+CD3+ cells, less than 1.0% of cellular impurities (viable CD45- and CD19+ cells), and a potency of more than 1.0×10^3 pg/mL IFN-γ secretion upon CD3/CD28-polymer stimulation. Across the tumor types, PD NTU101-DPs had comparable T-cell subset and differentiation state compositions. In vitro tumor-reactive potential was detected in 82% of tested NTU101-DPs (ENDC: 71%, n=5/7; NSCLC: 80%, n= 4/5; and PENC: 100%, n=5/5), although the level of reactivity will need to be confirmed with a more in-depth assay. One GMP NTU101-DP was then manufactured from each tumor type, and all three met NTU101's quality criteria.
Conclusion: The NTU101 platform produced comparable NTU101-DPs from three solid tumor types beyond melanoma, with in vitro tumor-reactive potential for some batches. This platform can be applied in TIL therapy clinical trials to generate ENDC-, NSCLC-, and PENC-derived TILs, and possibly other solid tumor types.

Keywords:  cellular therapy; good manufacturing practice; platform-based manufacturing; solid tumors; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1854761
Front Immunol. 2026 ;17 1908216

BCL2A1 marks an early, less-exhausted CD8+ tumor-infiltrating lymphocyte state associated with PD-1 blockade response in NSCLC.

Hoang Minh Quan Pham, Chia-Ling Chen, Po-Hao Feng, Kang-Yun Lee, Yu-Ping Hung, Chiou-Feng Lin.

   Background: The tumor microenvironment exerts intense survival pressure on CD8+ tumor-infiltrating lymphocytes (TILs), yet the cellular basis for an earlier, less-exhausted state associated with response to immune checkpoint blockade (ICB) in non-small-cell lung cancer (NSCLC) remains unclear. We previously identified BCL2A1 as a CD8+ TIL-derived marker predictive of a response to PD-1 blockade. Here we combine deep single-cell discovery with experimental validation in primary human T cells to characterise the BCL2A1-associated CD8+ TIL state and its candidate upstream signal.
Methods: We integrated four transcriptomic cohorts-pre-treatment bulk RNA-seq with CD8+ TIL deconvolution (n=60), on-treatment scRNA-seq/TCR-seq (n=11), longitudinal scRNA-seq/TCR-seq (n=18), and an independent post-treatment cohort (n=59)-with in silico perturbation, pathway, and metabolic-flux analyses, and experimentally tested a key prediction of this state by flow cytometry in primary human CD8+ T cells.
Results: BCL2A1high CD8+ TILs showed elevated BCL2A1 expression without coordinated upregulation of anti-apoptotic BCL2-family genes, maintained minimal exhaustion, and occupied an early, BCL6-, TCF7-, and NFKB1-regulated pseudotime state. Across longitudinal and post-treatment cohorts, they formed diverse, low-expansion repertoires rather than dominant expanded clones, with reduced biosynthetic flux (branched-chain amino acid and purine metabolism) consistent with a non-proliferative state. NF-κB signaling was elevated, and TNF-α was nominated as the leading candidate upstream ligand of BCL2A1. We then experimentally tested this prediction: in primary human CD8+ T cells, TNF-α induced BCL2A1 protein ≈13-fold (44.5% vs. 3.4% BCL2A1+; MFI 2.93-fold; P < 0.0001), whereas CD3/CD28 activation alone did not, establishing a TNF-α-specific, protein-level response.
Conclusions: Combining integrative single-cell analysis with experimental validation in primary human T cells, we define BCL2A1 as a marker of an early, less-exhausted CD8+ TIL state associated with improved ICB outcomes in NSCLC; a survival-related role is supported by these associations but was not functionally tested.

Keywords:  BCL2A1; CD8+ TIL; NSCLC; T-cell exhaustion; immune checkpoint blockade

DOI:  https://doi.org/10.3389/fimmu.2026.1908216
Cancer Res Commun. 2026 Oct 20.

Comparative analysis of ovarian cancer tumor-infiltrating T cells with those in melanoma and before and after PD-1 blockade.

Ilaria Colombo, Ksenia Meteleva, Simone C Stone, Anjelica Hodgson, Nicolas Jacquelot, Aras Toker, Azin Sayad, Jehan Vakharia, Valentin Sotov, Christine Tran, Hal K Berman, Stephenie Prokopec, Giselle Boukhaled, Lisa Wang, Pamela Soberanis Pina, Neesha Dhani, Amit M Oza, Marcus O Butler, Lillian L Siu, Ben X Wang, Pamela S Ohashi, Stephanie Lheureux.

CD8+ T cells are involved in natural tumor immune surveillance and are known to play a critical role in mediating responses to PD-1 blockade. High grade serous ovarian cancer (HGSOC) exhibits intrinsic resistance to immune-checkpoint inhibitors (ICI), despite the presence of tumor-infiltrating lymphocytes (TIL) in the tumor immune microenvironment (TIME). Here, we characterized the phenotype and frequency of TILs in the tumor samples of patients with HGSOC and compared our findings to TIL from melanoma (MEL), a tumor highly sensitive to ICI. MEL harboured an increased density of CD8+ TILs compared to HGSOC. However, CD8+ T cells from HGSOC tumor samples expressed higher levels of exhaustion markers such as 2B4 and PD-1 compared with the CD8+ MEL TILs, with the evidence for antigen- specific CD8+ TILs. Our study demonstrates that despite the presence of CD8+ T cells that are phenotypically exhausted, there is limited expansion of CD8+ cells after treatment with anti-PD-1 in patients with HGSOC. These data indicate that CD8+ T cells from ovarian cancer express markers associated with antigen specificity, are on the exhaustion trajectory, yet are unable to contribute to a measurable anti-tumor response after PD-1 blockade.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0011
Exp Hematol Oncol. 2026 Oct 22. pii: 109. [Epub ahead of print]15(1):

Innovations and emerging trends in adoptive cell therapies for solid tumors: engineering strategies and clinical translation.

Peng Huang, WenLin Wu, Yu Min, Yi Zhang, YunFeng Tao, Zheran Liu, Zhigong Wei, Xingchen Peng.

  Cancer remains a formidable challenge in global oncology, with conventional treatments often failing to achieve durable responses in advanced stages. Adoptive cell therapy (ACT), despite its revolutionary success in hematological malignancies, faces critical bottlenecks in solid tumors, including a hostile immunosuppressive tumor microenvironment (TME), restricted cellular trafficking, and the rapid onset of T-cell exhaustion. This review systematically explores the evolution of ACT platforms, ranging from foundational tumor-infiltrating lymphocytes (TILs) to precision-engineered chimeric antigen receptor (CAR)-T and T-cell receptor (TCR)-T therapies. We highlight how innovative engineering strategies such as the integration of "armored" CARs, synthetic gene circuits, and CRISPR/Cas9-mediated gene editing have been employed to enhance the persistence and polyfunctionality of effector cells. Beyond T-cell-centric approaches, we examine the emerging landscape of diverse immune effector cells, including CAR-natural killer (NK) cells, and CAR-macrophages (CAR-M), which offer unique advantages in antigen recognition and safety profiles. Furthermore, we detail the synergistic potential of multimodal combination regimens, where ACT is paired with immune checkpoint inhibitors (ICIs), localized radiotherapy, or nanotechnology-based delivery systems to dismantle TME barriers and achieve systemic anti-tumor immunity. By tracing the journey of therapeutic cells from ex vivo expansion to intratumoral infiltration and cytotoxicity, this review illuminates the molecular mechanisms governing therapeutic efficacy. Finally, we discuss the current clinical trial landscape, manufacturing hurdles, and the regulatory pathways essential for transitioning these sophisticated cellular products from bench to bedside.

Keywords:  Adoptive cell therapy; CAR-T cells; Combination immunotherapy; Genetic engineering; Solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-026-00848-3
Eur Arch Otorhinolaryngol. 2026 Oct 20.

Stromal tumor-infiltrating lymphocytes (sTIL) in laryngeal squamous cell carcinoma: association with pharyngocutaneous fistula, recurrence, and mortality.

Selçuk Erol, B Barış Büyük, Ayşegül Erol, Nazan Bozdoğan, Felat Toprak, Ayça Arslan.

   PURPOSE: Previous studies suggest a favorable prognostic role for tumor-infiltrating lymphocytes in laryngeal squamous cell carcinoma, although findings vary by immune-cell phenotype, assessment method, tumor compartment, and cohort characteristics. This study evaluated associations between sTIL percentage and pharyngocutaneous fistula, recurrence, and mortality after surgery.
METHODS: This single-center retrospective cohort included 81 patients who underwent primary or salvage total laryngectomy between January 2019 and March 2024. sTIL was assessed on H&E sections according to International TILs Working Group guidelines. Because sTIL was non-normally distributed (Shapiro-Wilk W = 0.908; p < 0.001), non-parametric tests were used. Associations were assessed using Mann-Whitney U, Kruskal-Wallis, chi-square/Fisher's exact tests, and Spearman correlation. Survival was analyzed using Kaplan-Meier and Cox regression.
RESULTS: Median sTIL was 30% (IQR: 10-50%). sTIL was not significantly associated with fistula, recurrence, mortality, surgical approach, lymphovascular or perineural invasion, T stage, or differentiation grade (all p > 0.05). Mortality was associated with older age (68 vs. 60 years; p = 0.004). Deceased patients had longer observed follow-up, reflecting time-to-event structure rather than a prognostic association. Kaplan-Meier analysis showed no survival difference by sTIL group (log-rank p = 0.914). In the reduced multivariable Cox model, age (HR: 1.05; p = 0.043) and lymphovascular invasion (HR: 4.79; p < 0.001) were independently associated with mortality, whereas sTIL was not (HR: 1.01; p = 0.600).
CONCLUSIONS: H&E-based sTIL scoring was not significantly associated with pharyngocutaneous fistula, recurrence, or overall survival. Given the limited number of fistula events, the fistula-related findings should be considered exploratory and hypothesis-generating. Age and lymphovascular invasion were independently associated with mortality. These non-confirmatory findings require validation in larger studies using spatial and phenotypic immune profiling.

Keywords:  Laryngeal squamous cell carcinoma; Mortality; Pharyngocutaneous fistula; Recurrence; Stromal tumor-infiltrating lymphocytes; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00405-026-10680-4
Oncogene. 2026 Oct 17.

Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy.

Yuma Fukumoto, Fumiaki Mukohara, Momoko Iwatsuru, Youki Ueda, Hiroaki Kanzaki, Sadahisa Ogasawara, Jason Lin, Masahito Kawazu, Toshifumi Ninomiya, Naoya Kemmotsu, Joji Nagasaki, Shinichi Toyooka, Tsuyoshi Osawa, Takamasa Ishino, Yosuke Togashi.

The combination immunotherapies, including those with atezolizumab and bevacizumab (Atez/Bev), have become standard therapy for hepatocellular carcinoma (HCC). However, its efficacy remains limited and reliable biomarkers are lacking. In this study, we analyzed paired tumor and background liver tissues from Atez/Bev-treated HCC patients and found that high programmed cell death-1 (PD-1) expression in CD8+ tumor-infiltrating lymphocytes (TILs) correlated with therapeutic response independent of etiology. RNA sequencing on the tumor samples revealed that the branched-chain amino acid (BCAA)-related metabolic pathway was enriched in the group with high PD-1 expression in CD8⁺ TILs. Along with in vitro experiments, we identified the importance of BCAAs for activation and differentiation of CD8+ T cells. In addition, BCAA metabolism was related to response to PD-1 blockade in not subcutaneous but intrahepatic mouse model-specific manner. Actually, public dataset analyses revealed that high expression of BCAT1, a key enzyme in BCAA metabolism, was associated with poor prognosis in HCC, but not in other cancer types. These findings suggest the importance of liver-specific BCAA metabolism in antitumor immunity and highlight the need to assess the tumor microenvironment within its organ-specific metabolic context.

DOI: https://doi.org/10.1038/s41388-026-04023-0
Oncology. 2026 Oct 22. 1

Predicting Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer Using Machine Learning of MRI Radiomics.

Xu Kai, Keqing Li.

OBJECTIVE: To develop and validate a machine learning-based MRI radiomics model for predicting the risk of non-pathological complete response (non-pCR) following neoadjuvant chemotherapy in breast cancer, to identify independent influencing factors.
METHODS: A total of 400 consecutive breast cancer patients were randomly divided into training and validation sets at a 7:3 ratio. Baseline clinicopathological variables, functional magnetic resonance imaging (MRI) parameters, tumor-infiltrating lymphocytes (TILs), and longitudinal MRI radiomics scores were collected. Variables were selected using univariate analysis and least absolute shrinkage and selection operator (LASSO) regression. Random forest, support vector machine, and logistic regression models were constructed and evaluated using area under the curve (AUC), calibration, decision curve analysis, and SHapley Additive exPlanations (SHAP) interpretation.
RESULTS: Multivariate logistic regression confirmed all six factors (Ki-67 proliferation index, maximum tumor diameter, apparent diffusion coefficient (ADC) value, initial enhancement rate, tumor-infiltrating lymphocytes (TILs), and radiomics score) as independent predictors of non-pCR (P < 0.05). The random forest model showed the numerically highest AUC, with an AUC of 0.835 [95% confidence interval(CI): 0.767-0.904] in the training set and 0.745 (95% CI: 0.597-0.893) in the validation set, outperforming logistic regression (training: 0.805; validation: 0.717) and support vector machine (training: 0.792; validation: 0.702). SHAP analysis revealed that feature contributions, in descending order, were as follows: radiomics score, ADC value, initial enhancement rate, TILs, Ki-67 proliferation index, and maximum tumor diameter. SHAP analysis identified radiomics score, ADC value, and initial enhancement rate as the leading contributors.
CONCLUSIONS: The random forest model constructed in this study, integrating MRI radiomics and functional imaging parameters, exhibits acceptable discrimination and calibration for predicting pathological response to neoadjuvant chemotherapy in breast cancer.

DOI: https://doi.org/10.1159/ocl/aebag026
Balkan Med J. 2026 Oct 19.

HPV16 E7-Containing Exosomes May Contribute to PD-L1 Expression in Tumor-Infiltrating Lymphocytes of Cervical Cancer.

Yajing Zhang, Guqun Shen, Li Luo, Yangchun Feng, Senyu Wang.

Background: Human papillomavirus 16 (HPV16) plays a major role in the development of cervical cancer (CC). Programmed cell death ligand 1 (PD-L1) expression in tumor-infiltrating lymphocytes (TILs) is an important feature of the tumor immune microenvironment and may affect responses to immune checkpoint blockade. However, the relationship between the HPV16 E7 oncoprotein and PD-L1 expression in TILs remains unclear.
Aim: To investigate the presence of HPV16 E7 protein in exosomes from CC tissues and plasma, determine the association between exosomal E7 and PD-L1 expression in TILs, and explore whether E7-rich tumor-derived exosomes contribute to increased PD-L1 expression in TILs.
Study Design: This study combined clinical observational analyses and in vitro experiments. Three CC single-cell RNA sequencing datasets, a 30-patient HPV16-positive cohort, and a 104-patient tissue microarray cohort were analyzed. In vitro experiments were conducted to further examine the potential relationship between exosomal E7 and PD-L1 expression in TILs.
Methods: Blood and pathological samples from 30 patients with HPV16-positive CC, as well as culture fluid from the C33A and SiHa CC cell lines, were collected. Exosomes were isolated, and E7 protein expression was assessed. Bioinformatics analyses of CC single-cell RNA sequencing datasets were performed to evaluate CD274 mRNA expression in TILs. Immunohistochemistry (IHC) was used to assess PD-L1 protein expression in TILs in the 30-patient cohort, while multiplex immunofluorescence was used to evaluate E7 and PD-L1 expression in TILs in a 104-patient tissue microarray. Exosome uptake by TILs was assessed using confocal microscopy. TILs were co-cultured with exosomes, and HPV16 E7 and PD-L1 expression was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting in the TIL blank control, co-culture blank control, co-culture empty vector, and co-culture E7-overexpression groups.
Results: E7 protein was detected in exosomes from the peripheral blood of 28 of 30 patients (93.3%) and in exosomes from SiHa cell culture. PD-L1 was expressed in TILs, with a positive rate of 43.3% (13/30). In the tissue microarray cohort (n = 103; 28 events), higher CD3+PD-L1+/CD3+ expression was associated with poorer survival (HR = 2.97, p = 0.009). CD3+E7+/CD3+ expression showed a borderline association with poorer survival in the dichotomized analysis (HR = 2.15, p = 0.052) but was significantly associated with survival when modeled as a continuous variable (per 10%: HR = 1.28, p = 0.002). In the 30-patient cohort, exosomal E7 protein content was significantly associated with PD-L1 expression in TILs (Cramér's V = 0.728, p = 0.0001). qRT-PCR and western blotting demonstrated increased PD-L1 mRNA and protein expression in TILs exposed to exosomes from E7-overexpressing cells.
Conclusion: HPV16 E7 protein is present in exosomes from patients with CC and HPV16-positive CC cells. Higher exosomal E7 levels are associated with increased PD-L1 expression in TILs, and exposure to E7-rich exosomes is associated with upregulated PD-L1 expression in TILs. These findings suggest that exosomal E7 may contribute to PD-L1 regulation in TILs and may be associated with poorer prognosis in patients with CC. Further studies are needed to determine whether E7 directly mediates this effect and to clarify its functional and clinical significance.

DOI: https://doi.org/10.4274/balkanmedj.galenos.2026.2026-6-20
Nat Commun. 2026 09 18. pii: 10953. [Epub ahead of print]17(1):

Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors.

Nathan Vaudiau, Pierre Bourdely, Maria Semitekolou, Agathe Ok, Louise Gorline, Aboubacar Sidiki K Coulibaly, Matthieu Rastello, Aurélie Semervil, Roberto Savoldelli, Yohan Gerber-Ferder, Fillipe Luiz Rosa do Carmo, Mathias Vétillard, Audrey Rood, Jérémie Bornères, Abdenour Abbas, Marie Guillin, Judith Weber, Syrine Bouallegue, Konstantina Pamboukas, Zacarias Garcia, Florent Ginhoux, Camille Blériot, Philippe Bousso, Yosuke Kumamoto, Guillaume Darrasse-Jèze, Emmanuel L Gautier, Marc Dalod, Eric Tartour, Tessa Bergsbaken, Klaas P J M Van Gisbergen, Kairbaan M Hodivala-Dilke, Massimiliano Mazzone, Loredana Saveanu, Julie Helft, Federica Benvenuti, Pierre Guermonprez.

Tumor-infiltrating tissue-resident memory (TRM)-like CD8+ T cells correlate with positive prognosis and better responses to cancer immunotherapy, yet the mechanisms underlying their specification remain ill-understood. Here, we use the KP (KrasG12D, p53-/-) mouse model of lung adenocarcinoma to investigate how different dendritic cell (DC) subsets shape tumor-specific CD8+ T cell responses. Selective ablation of XCR1+ DC1s or IRF4-dependent CD11b+ DC2s reveal that DC1s, but not DC2s, are required for the generation of tumor-infiltrating effector and exhausted CD8+ T cells. By contrast, both migratory DC1s and migratory DC2s contribute to the specification of CD103+CD69+ TRM-like CD8+ T cells in tumor-draining lymph nodes. Mechanistically, low peptide/MHC-I density on migratory DC2s favors TGFβ-dependent TRM differentiation, while high peptide/MHC-I density on DC1s promote proliferative expansion of TRM-like cells; in addition, IL-12 secreted by DC1s enhances CXCR6 expression. Together, our findings uncover complementary functions of migratory DC subsets in shaping anti-tumor TRM-like CD8+ T cell responses, and also implicate targeting multiple DC subsets for optimizing cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-026-77641-7
Front Oncol. 2026 ;16 1893983

A multimodal deep learning radiomics nomogram integrating clinicopathological features for predicting pathological complete response after neoadjuvant therapy in triple-negative breast cancer: a multicenter retrospective study.

Chuanchuan Qi.

   Background: Accurate noninvasive estimation of pathological complete response (pCR) after neoadjuvant therapy (NAT) in triple-negative breast cancer (TNBC) may support multidisciplinary discussions, but multimodal MRI-ultrasound evidence remains limited. We developed and externally validated a clinicopathological deep learning radiomics nomogram and explored its potential auxiliary value in a strictly hypothetical post-hoc surgical-planning scenario.
Methods: With institutional review-board approval and waived consent, this retrospective multicenter diagnostic accuracy study included 436 biopsy-proven TNBC patients who underwent NAT and surgery: Center 1 training cohort (n = 268) and internal validation cohort (n = 86), plus historical cases from cooperating Centers 2-3 for external validation (n = 82). pCR was defined as ypT0/is ypN0. Pretreatment dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) maps, T2-weighted imaging (T2WI), and B-mode ultrasound were analyzed. Intratumoral and 5-mm peritumoral ring radiomics features were extracted and selected by LASSO. DenseNet-121 extracted modality-specific deep features, fused using multi-head self-attention. Age, tumor size, Ki-67, tumor-infiltrating lymphocytes (TILs), cT/N stage, and histological grade were integrated with imaging scores in a logistic-regression nomogram. Parameters and thresholds were locked after Center 1 development and applied once to external data. No model output was used clinically. Feature standardization and ComBat harmonization parameters were strictly locked to the training cohort before application to validation data.
Results: pCR occurred in 182/436 patients (41.7%). The nomogram achieved areas under the receiver operating characteristic curve (AUCs) of 0.917 (95% CI, 0.881-0.947) in training, 0.883 (0.814-0.937) in internal validation, and 0.856 (0.773-0.921) in external validation, exceeding clinical (external AUC, 0.721), radiomics (0.786), and deep learning (0.819) models. External sensitivity, specificity, and accuracy at the locked threshold were 0.765, 0.813, and 0.793, respectively. Calibration was acceptable (slope, 0.93; intercept, -0.06; Brier score, 0.16). Decision curve analysis showed net benefit for thresholds of 0.20-0.70. Multi-threshold analysis revealed that a high-specificity threshold (0.65) yielded a positive predictive value of 0.85, potentially identifying a subset of patients with very high confidence of achieving pCR. Compared with the clinical model, external reclassification improved (continuous net reclassification improvement [NRI], 0.34; integrated discrimination improvement [IDI], 0.11; P = 0.003 and P = 0.008, respectively).
Conclusion: Among the few multicenter TNBC studies combining MRI, ultrasound, intratumoral/peritumoral radiomics, and attention-based deep learning, this nomogram showed good retrospective accuracy for pCR prediction after NAT. The model is presented as an aid for pCR prediction and preoperative stratification rather than as direct support for surgical decision-making. Prospective validation and clinical-impact studies are required before implementation.

Keywords:  deep learning; multimodal imaging; neoadjuvant therapy; nomogram; pathological complete response; radiomics; triple-negative breast cancer

DOI:  https://doi.org/10.3389/fonc.2026.1893983
Med. 2026 Oct 20. pii: S2666-6340(26)00334-X. [Epub ahead of print] 101331

Systemic antitumor responses to hypofractionated radiotherapy plus Poly(I:C) in advanced hepatocellular carcinoma: A phase 2 trial.

Liman Qiu, Qizhen Huang, Xinting Pan, Geng Chen, Wenhui Liu, Kai Wang, Yang Zhou, Rong Xie, Xiuqing Dong, Qiming Wu, Zhenli Li, Yongyi Zeng, Hongbing Ji, Zhixiong Cai, Xiaolong Liu.

   BACKGROUND: The abscopal effect, regression of unirradiated tumors after localized radiotherapy, is rare. Whether hypofractionated radiotherapy (HFRT) plus the innate immune agonist polyinosinic-polycytidylic acid [Poly(I:C)] amplifies systemic antitumor immunity in advanced hepatocellular carcinoma is unclear.
METHODS: In this single-arm, phase 2 trial (ChiCTR2100053441), 37 patients received HFRT plus subcutaneous Poly(I:C); 33 were response evaluable. Outcomes were compared with 33 propensity score-matched patients treated with HFRT alone. The primary endpoint was the objective response rate per RECIST v.1.1; secondary endpoints included progression-free survival, overall survival, and safety; and abscopal response was prespecified. Mechanisms were explored by single-cell RNA sequencing and flow cytometry in patients and by CD8 depletion and CD28 blockade in mice.
FINDINGS: HFRT plus Poly(I:C) was well tolerated; it was associated with a higher objective response rate (54.5% vs. 21.2%; p = 0.011) and abscopal response rate (45.0% vs. 10.5%; p = 0.042) as well as longer progression-free survival (8.4 vs. 4.6 months; adjusted hazard ratio = 0.542; p = 0.042) and overall survival (not reached vs. 13.6 months; adjusted hazard ratio = 0.386; p = 0.011) vs. HFRT alone. The progression-free survival benefit was also higher in patients concurrently receiving tyrosine kinase inhibitors (p for interaction = 0.013). Peripheral CD8+CD28+ T cell expansion correlated with abscopal tumor control; in mice, CD8+ T cells and CD28 co-stimulation were required for this effect.
CONCLUSIONS: HFRT plus Poly(I:C) showed promising systemic antitumor activity with manageable safety in advanced hepatocellular carcinoma, with CD8+CD28+ T cells as an immune correlate of response. These exploratory findings warrant confirmation in randomized trials.
FUNDING: The National Natural Science Foundation of China.

Keywords:  CD8(+)CD28(+) T cells; Translation to patients; abscopal effect; hepatocellular carcinoma; polyinosinic-polycytidylic acid; radiotherapy; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.medj.2026.101331
Lab Invest. 2026 Oct 23. pii: S0023-6837(26)00104-2. [Epub ahead of print] 106174

Stromal B7-H3 Expression Characterizes an Immune-Hot Microenvironment and Predicts Response to PD-1 Blockade in Gastric Cancer.

Ruipeng Wang, Yunwen Tao, Hanqin Xuan, Hao Zhang, Qiange Zhang, Feng Zhang, Jinjing Xu, Lili Huang, Yunyun Xu, Shenghua Zhan, Lei Cao, Ling Gao.

   PURPOSE: We evaluated whether B7-H3, particularly stromal B7-H3, is associated with clinical benefit from programmed cell death protein 1 (PD-1) blockade in gastric cancer (GC) and characterized the immune context underlying this association.
MATERIALS AND METHODS: B7-H3 expression was evaluated by conventional and multiplex immunohistochemistry (m-IHC) in a discovery cohort of 124 patients with GC receiving PD-1 inhibitor-based therapy and in an independent single-center validation cohort of 40 patients. Associations with treatment response and progression-free survival (PFS) were assessed using categorical tests, Kaplan-Meier analysis, and Cox regression. An exploratory cohort of 40 patients who had not received PD-1 blockade was analyzed to assess the general prognostic association of B7-H3. Host B7-H3 was further examined in a subcutaneous mouse forestomach carcinoma (MFC) tumor model using Cd276-deficient mice, with immune profiling and RNA sequencing after PD-1 blockade.
RESULTS: In the discovery cohort, B7-H3 expression was significantly higher in responders (P < 0.0001), and high B7-H3 expression was associated with longer PFS (P = 0.0030). In the validation cohort, the objective response rate was 64.0% in the B7-H3-high group versus 26.7% in the B7-H3-low group (P = 0.0484), and B7-H3-high patients had longer PFS (P = 0.0315). Cell-type-specific m-IHC showed stronger associations for B7-H3+/α-SMA+, B7-H3+/CD31+, and B7-H3+/CD68+ stromal compartments than for B7-H3+/PanCK+ tumor cells. B7-H3 also correlated positively with PD-L1 and triplet cell cluster (TCC) infiltration. In the exploratory non-PD-1 cohort, high B7-H3 expression showed a nonsignificant trend toward higher mortality (HR = 1.548, 95% CI 0.932-2.571, P = 0.091). Following PD-1 blockade, wild-type tumors showed greater tumor control and higher CD8+, CD4+, and natural killer (NK)-cell infiltration than Cd276-deficient tumors.
CONCLUSIONS: Stromal B7-H3 is a candidate biomarker associated with favorable outcomes after PD-1 blockade and may mark an immune-engaged microenvironment with pre-existing immune-cell infiltration. These findings support prospective, multicenter evaluation of B7-H3 for patient stratification rather than establishing it as a clinically validated companion diagnostic.

Keywords:  B7-H3; PD-1 blockade; candidate predictive biomarker; gastric cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.labinv.2026.106174
Cancer Cell. 2026 Oct 22. pii: S1535-6108(26)00435-6. [Epub ahead of print]

Lung neuroendocrine cancer induces immunosuppressive macrophages via serotonin to drive resistance to the T cell engager tarlatamab.

Kotaro Nomura, Tomoyo Fukami, Shinichiro Kato, Shunya Tanaka, Akito Fukuda, Yuki Koike, Masaki Kondo, Kazuhiro Kumagai, Takuma Irie, Genki Okumura, Tetsuro Taki, Shingo Sakashita, Masayuki Shirasawa, Tatsuya Yoshida, Kouya Shiraishi, Ryo Ariyasu, Yuki Takeyasu, Takahiro Niimi, Tetsuya Sakai, Masahiro Torasawa, Hiroaki Kanemura, Shin Saito, Takuo Hayashi, Akinori Kanai, Kazuya Takamochi, Tomohiro Haruki, Keiju Aokage, Hitomi Nishinakamura, Shohei Koyama, Genichiro Ishii, Yutaka Suzuki, Yasushi Goto, Makoto Nishio, Kenji Suzuki, Yasuhiro Tsutani, Yasushi Yatabe, Hiroyuki Mano, Masahiro Tsuboi, Shogo Kumagai, Hiroyoshi Nishikawa.

  Tarlatamab, a delta-like protein 3 (DLL3) × CD3-directed T cell engager (TCE), provides clinical efficacy against small cell lung cancers (SCLCs), although its efficacy remains limited, indicating the importance of clarifying the resistance mechanisms. We show that serotonin (5-HT) produced by DLL3high neuroendocrine cancers (NECs) induces immunosuppressive tumor-associated macrophages (TAMs), resulting in impaired CD8+ T cell function and TCE resistance. Using SCLC and large cell neuroendocrine carcinoma cohorts, we find that DLL3high SCLCs induce immunosuppressive TAMs in the tumor microenvironment and become resistant to tarlatamab. DLL3high NECs increase 5-HT production via TPH1 upregulation. NEC-derived 5-HT augments the immunosuppressive activity of 5-HT receptor 7 (HTR7)-expressing TAMs. Genetic ablation of HTR7 in TAMs or TPH1 in NECs restores CD8+ T cell function and improves the efficacy of TCEs and programmed cell death protein 1 (PD-1) blockade. We propose that NEC-derived 5-HT-HTR7 axis drives immunosuppressive TAM activation and TCE resistance, making it a key target to increase TCE efficacy.

Keywords:  DLL3; T cell engager; neuroendocrine carcinoma; serotonin; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2026.09.016
Int J Med Sci. 2026 ;23(11): 3464-3482

State-Dependent Decoupling of a CREM-Centric cAMP-Responsive Regulon and Survival in Hepatocellular Carcinoma.

Hao Ling, Yanzhu Hu.

   Background: The cAMP-responsive element modulator (CREM) has emerged as a cAMP-responsive transcriptional node associated with dysfunctional lymphocyte states in chronic hepatic infection and some immunosuppressive tumor microenvironments, but its regulatory output and isoform usage by specific cell-types remain insufficiently defined in hepatocellular carcinoma (HCC). Because CREM produces activating isoforms and repressive inducible cAMP early repressor (ICER) isoforms through alternative promoter usage, bulk or single-cell CREM mRNA abundance may not faithfully describe the net direction of downstream CRE-dependent transcriptional programs.
Methods: Single-cell RNA-seq datasets spanning 18,665 T cells from two independent, pathologically validated primary liver cancer cohorts (32 HCC and 5 iCCA patients) were integrated, with HCC-only sensitivity analyses confirming the primary findings. Using prior-knowledge transcriptional regulon frameworks cross-referenced with CRE-family genomic occupancy data (ENCODE), CREM mRNA expression was decoupled from its inferred downstream regulon activity at single-cell resolution. Validation was performed using a third-generation long-read direct RNA sequencing hepatic model and bulk TCGA clinical survival cohorts.
Results: Across multiple regulon definitions, single-cell CREM mRNA and regulon activity were characterized by prominent low-coupling at the single-cell level (meta-Spearman ρ < 0.20, explaining <4% of variance). Crucially, this low-coupling was not uniform but followed a continuous T-cell state gradient, where the correlation between CREM expression and target activation progressively tightened as T cells transitioned from a resting state toward an activated or exhausted phenotype. Long-read direct RNA sequencing in a hepatic lineage reference model revealed that the activation-associated P1 promoter (CREMτ) predominated over the repressor-associated P2 promoter (ICER) by a 14:1 ratio under steady states. In bulk TCGA-LIHC data, elevated CREM-centric regulon scores, but not raw mRNA levels, correlated with favorable overall survival (HR = 0.787, p = 0.026), operating primarily as a T-cell activation- and infiltration-associated prognostic feature rather than an independent cell-autonomous biomarker.
Conclusions: Single-cell CREM mRNA abundance is not a reliable proxy for its transcriptional output in HCC tumor-infiltrating lymphocytes. Instead, the coupling between CREM expression and its regulon activity is dynamically modulated by the T-cell activation state, a phenomenon partially explained by the usage of alternative isoforms in reference models. These findings caution against the routine practice of translating crude transcription factor mRNA metrics directly into functional regulatory inputs within a complex tumor immune microenvironment.

Keywords:  cAMP-responsive element modulator (CREM); hepatocellular carcinoma; long-read sequencing; single-cell RNA sequencing; transcription-factor regulon; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.7150/ijms.140851
Annu Rev Med. 2026 Oct 23.

T Cell Receptor-Engineered T Cell Therapy in Solid Tumors: Where We Stand and What's to Come.

Candela Ferriol-Martínez, Sandra P D'Angelo.

T cell receptor-engineered T (TCR-T) cell therapy has emerged as a promising adoptive cellular therapy for solid tumors by enabling recognition of intracellular antigens presented via human leukocyte antigen (HLA) molecules. Unlike chimeric antigen receptor T cell therapy, TCR-T cell therapy targets a broader antigen repertoire, including cancer-testis antigens, neoantigens, and viral antigens. Recent clinical advances, highlighted by the approval of afamitresgene autoleucel in synovial sarcoma, demonstrate meaningful antitumor activity. However, several limitations remain, including HLA restriction, antigen heterogeneity, toxicity related to on-target/off-tumor effects, and mechanisms of resistance such as antigen loss and T cell exhaustion. Advances in antigen selection, gene editing, and synthetic biology are improving both safety and efficacy. Combination strategies and next-generation engineered constructs are expected to overcome current barriers. This review summarizes the biological rationale, clinical evidence, safety considerations, and resistance mechanisms of TCR-T cell therapy in solid tumors and discusses future directions to optimize their therapeutic potential.

DOI: https://doi.org/10.1146/annurev-med-042425-051841
Cancer Lett. 2026 Oct 22. pii: S0304-3835(26)00690-7. [Epub ahead of print] 218926

Fenofibrate enhances systemic antitumor efficacy of high- and low-dose radiotherapy plus PD-1 blockade through CD8+ T-cell metabolic reprogramming and LDRT tumor conditioning.

Meidan Wang, Liqun Wang, Sagar, Xi Rao, Naghmeh Shirafkan, Yizhou Yang, Simone Gaedicke, Anca-Ligia Grosu, Elke Firat, Gabriele Multhoff, Gabriele Niedermann.

  Radiotherapy (RT) combined with PD-1/PD-L1 blockade can induce systemic antitumor responses, but robust control of distant lesions remains uncommon. We identified a quadruple regimen combining immunogenic hypofractionated RT (hRT; 8 Gy × 3) to the primary tumor, low-dose RT (LDRT; 3 Gy × 3) to the secondary tumor, anti-PD-1 (αPD-1), and fenofibrate (FFB), a clinically approved PPARα agonist, that enhanced antitumor efficacy in two bilateral tumor models. Only this regimen substantially improved secondary-tumor control, eradicating LDRT-treated secondary tumors in all mice in the immunologically cold C51 model and inducing prolonged control in the aggressive, αPD-1-poorly responsive B16-CD133 model. This effect required CD8+ T cells. Tumor-specific CD8+ TILs showed enhanced effector function, reduced exhaustion, increased mitochondrial fitness, and a shift toward mitochondrial fatty acid oxidation (FAO), with scRNA-seq supporting PPARα/FAO-associated remodeling, including upregulation of Cpt1a, encoding the FAO enzyme CPT1A, in effector-associated, proliferative, and clonally expanded subsets. Both antitumor efficacy and T-cell metabolic remodeling were reversed by the CPT1 inhibitor etomoxir. By contrast, LDRT impaired tumor-cell mitochondrial fitness, while FFB shifted tumor cells from FAO toward glycolytic reliance and induced only slight apoptosis. Consistently, in vivo data argued against direct LDRT-mediated tumor-cell debulking. The quadruple regimen increased vascular MECA-79 expression, while LDRT enhanced endothelial ICAM-1/VCAM-1 and tumor-cell CXCL9/CXCL10 expression in secondary tumors, consistent with local conditioning favoring T-cell recruitment. These findings highlight FFB as a clinically tractable metabolic modulator and link FFB-enhanced hRT/LDRT/αPD-1-induced systemic antitumor efficacy to metabolic reprogramming of tumor-specific CD8+ TILs and conditioning of the LDRT-treated tumor microenvironment.

Keywords:  PPARα-agonism; fatty acid oxidation; immune checkpoint inhibitors; low-dose radiation; systemic effects of radiotherapy

DOI:  https://doi.org/10.1016/j.canlet.2026.218926
ESMO Open. 2026 Oct 21. pii: S2059-7029(26)02549-4. [Epub ahead of print]11(11): 108604

Parity, breastfeeding, and reproductive timing are associated with tumour-infiltrating lymphocytes in hormone receptor-negative breast cancer: a population-based cohort study.

E Gabrielsen, A Wirsing, T Wilsgaard, I Thune, H Frydenberg, T Lofterød, E Mortensen, H Nalwoga, L A Akslen, H S Haugnes, E S Blix.

   BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are established biomarkers of breast cancer immunogenicity and prognosis. Reproductive events induce durable immunological remodelling of the breast, but whether TIL levels at diagnosis reflect the immunological imprint of these events remains unclear.
MATERIALS AND METHODS: We included women diagnosed with invasive breast cancer between 1978 and 2012 in the Energy Balance and Breast Cancer Aspects throughout Life study, a substudy of the population-based Tromsø Study (Norway). Prediagnostic host factors were obtained. TILs were scored on an ordinal scale (1-4). Associations between host factors and the TIL score were analysed using ordinal logistic regression with interaction terms for hormone receptor (HR) status. Breast cancer-specific mortality was evaluated using Kaplan-Meier methods and Cox regression.
RESULTS: A total of 425 women were included [median age at diagnosis 56.0 years, 360 (87.6%) parous], of whom 84 (19.8%) had HR-negative tumours. Among HR-negative cases, parity [odds ratio (OR) 10.14, 95% confidence interval (CI) 1.97-52.22], longer breastfeeding duration [OR 1.87 per standard deviation (SD), 95% CI 1.10-3.17], and higher age at first birth (OR 1.79 per SD, 95% CI 1.06-3.01) were associated with higher TIL scores, whereas higher mean arterial pressure (OR 0.59 per SD, 95% CI 0.41-0.86) was inversely associated. Significant interactions with HR status were observed for parity and breastfeeding duration. No associations were observed in HR-positive tumours. High-TIL levels (scores 3-4 versus 1-2) were associated with lower breast cancer-specific mortality in HR-negative tumours (adjusted hazard ratio 0.32, 95% CI 0.14-0.72) but not in HR-positive disease (hazard ratio 0.98, 95% CI 0.58-1.68; Pinteraction = 0.023).
CONCLUSIONS: These findings suggest that reproductive history and timing may shape the tumour immune microenvironment over the life course. If confirmed in larger studies, TILs may represent an intermediate phenotype linking upstream host characteristics to downstream clinical outcomes in breast cancer.

Keywords:  breast cancer; breastfeeding; clinical outcomes; parity; tissue microarray; tumour-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.esmoop.2026.108604
Int J Biol Sci. 2026 ;22(15): 8476-8491

Radiotherapy Reprograms CCR8⁺ Regulatory T Cells via REL-NF-κB to Enforce Spatial Immune Exclusion in Hepatocellular Carcinoma.

Huanliang Chen, Shuxuan Wang, Bufu Tang, Yanyan Lin, Pan Zhou, Jiaoyang Yang, Qian-Qian Zhao, Zhao-Chong Zeng.

  Radiotherapy is increasingly incorporated into the treatment of hepatocellular carcinoma (HCC), but adaptive immunosuppressive remodeling of the tumor microenvironment can limit efficacy. We integrated public bulk, single-cell, and spatial transcriptomic cohorts with a murine single-cell atlas, paired human radiotherapy specimens, and functional murine studies. High intratumoral regulatory T cell (Treg) infiltration was associated with poor prognosis across two cohorts. Analyses of single cells identified a CCR8⁺ Treg state that was enriched in advanced tumors, exhibited enhanced suppressive features, and was conserved across species. Spatial analyses showed that CCR8⁺ Tregs accumulated in peritumoral regions enriched in myeloid cells and fibrotic stroma, where CD8⁺ T cell infiltration was limited. Hypofractionated radiotherapy expanded suppressive CCR8⁺ Tregs, while radiation enhanced CCL1 secretion by M2-like tumor-associated macrophages (TAMs), providing a recruitment signal. Mechanistically, REL knockdown, chromatin immunoprecipitation, and promoter reporter assays demonstrated that radiation activates REL, which directly binds to and transactivates the CCR8 promoter. CCR8 blockade enhanced radiotherapy efficacy, reduced suppressive Treg features, and increased cytotoxic CD8⁺ T cell activity. These findings identify a REL-NF-κB-CCR8 axis as a mediator of immune adaptation following radiotherapy and support combination therapies targeting CCR8 in HCC.

Keywords:  CCR8; Tregs; hepatocellular carcinoma; immunotherapy

DOI:  https://doi.org/10.7150/ijbs.136364
Immunother Adv. 2026 ;6(1): ltag012

Cellular immunotherapy for acute myeloid leukemia: from bench to bedside.

Yu Wang, Jiaying Wu, Xiaobing Huang, Yi Xiao.

  Acute myeloid leukemia (AML) is a clonal malignant disease that arises from hematopoietic stem cells and is characterized by high genetic heterogeneity. AML has a poor prognosis, with a low 5-year survival rate, and is typically treated with chemotherapy. The management of AML, particularly for cases that are relapsed or refractory to conventional chemotherapy and transplantation, remains a formidable clinical challenge. This comprehensive review systematically evaluates the current landscape of cellular immunotherapeutic strategies for AML. We focus on the mechanisms of action, recent clinical progress, and persistent challenges associated with a range of adoptive cell therapies. These include natural killer cell-based infusions, and engineered approaches such as chimeric antigen receptor-T, CAR-NK, and CAR-macrophage therapies. Furthermore, we examine the roles of tumor-infiltrating lymphocytes and cytokine-induced killer cells. Our analysis synthesizes evidence from preclinical studies and clinical trials to assess the potential of these modalities in inducing durable antileukemic responses. We conclude that while cellular immunotherapies represent a transformative frontier in AML treatment, their broad application is currently constrained by target antigen heterogeneity, a complex tumor microenvironment, and significant toxicities. Finally, this review discusses strategic innovations necessary to overcome these barriers, highlighting directions for future research aimed at enhancing the efficacy and safety of these promising treatments for AML patients.

Keywords:  acute myeloid leukemia; chimeric antigen receptor T-cell therapy; chimeric antigen receptor macrophage therapy; chimeric antigen receptor natural killer cell therapy; cytokine-induced killer cells; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/immadv/ltag012
Nat Commun. 2026 09 16. pii: 10882. [Epub ahead of print]17(1):

A modular synthetic promoter toolkit for programmable gene control in activated and chronically stimulated T cells.

Giuliano Bonfá, Giovanna Martino, Assunta Sellitto, Juan Luis Blazquez-Roman, Fabiana Tedeschi, Antonio Rinaldi, Caio Raony Farina Silveira, Francesca Piro, Fabio Caliendo, Loris Melchiorri, Daniela Perna, Rita Tarnai, Christoph Heuser-Loy, Fabio Mastrogiovanni, Timea Vadász, Freddie Starkey, Evangelos Nikolados, Filippo Menolascina, Luca Gattinoni, Velia Siciliano.

Synthetic circuits that couple transgene expression to endogenous transcription factor (TF) activity enable cellular response to changing functional states. In T cells, antigen stimulation results in dynamic changes of transcription factor expression programs. Harnessing these endogenous TF dynamics for programmable gene control remains an important challenge in engineered T cells. Here, we develop a library of synthetic promoters (SPs) responsive to seven TFs identified through transcriptomic analysis of T-cell activation programs. These promoters couple endogenous TF activity to transcriptional output across a broad dynamic range of inducibility and basal expression. We quantitatively profile promoter performance in HEK293 and Jurkat cells, evaluate them for orthogonality, and integrate them into Boolean logic gate architectures and network topologies to minimize basal transcriptional leakiness and improve ON/OFF ratios. We test selected synthetic promoters in primary human CD8⁺ T cells, under endogenous TF regulation, and we further characterize the NR4A2-responsive promoter subset in vitro and in tumor-infiltrating engineered T cells in a melanoma xenograft model, demonstrating dynamic and reversible activation.Together, these results provide a modular SP toolkit of TF-responsive synthetic promoters for programmable transcriptional control in engineered T cells.

DOI: https://doi.org/10.1038/s41467-026-77730-7
Front Immunol. 2026 ;17 1946712

Pimozide enhances antigen cross-presentation and promotes cytotoxic CD8+ T cell immunity by stimulating dendritic cells.

Luz María Palacios, Nicolás Daniel Dho, Cintia Liliana Araujo Furlán, Guadalupe López Menichetti, Federico Ruiz Moreno, Laura Guantay, Sofía Daiana Castell, María Esperanza Felici, Gastón Soria, Belkys Maletto, María Inés Crespo, Gabriel Morón.

  The activation of cytotoxic CD8+ T cells requires antigen presentation in the context of major histocompatibility complex class I (MHC-I). While endogenous antigens can directly access this pathway, the priming of CD8+ T cells against exogenous antigens-such as those derived from tumors or internalized pathogens-depends on dendritic cell (DC)-mediated antigen cross-presentation. Strategies capable of enhancing DC cross-presentation are therefore of considerable interest for the development of next-generation immunotherapies. Here, we demonstrate that pimozide, a clinically approved antipsychotic with reported antitumoral and immunomodulatory properties, acts as a pharmacological enhancer of antigen cross-presentation. We show that pimozide-treated DCs display improved cross-presentation of soluble antigens, leading to stronger CD8+ T cell activation and proliferation in vivo, enhanced IFN-γ production by antigen-specific CD8+ T cells in vitro, and augmented cytotoxic T lymphocyte responses in vivo. Mechanistically, pimozide reshapes antigen-processing pathways in DCs by increasing reactive oxygen species production and altering endosomal physiology, thereby creating a biochemical environment that favors antigen cross-presentation. Moreover, pimozide treatment reduces STAT5 levels in DCs, and pharmacological inhibition of STAT5 with an independent inhibitor recapitulates the enhancement of cross-presentation and CD8+ T cell activation, suggesting STAT5 signaling as a mediator of this effect. Together, these findings reveal an unrecognized immunomodulatory activity of pimozide on DCs and establish a conceptual framework for the pharmacological repositioning of small molecules to reprogram DC function. This work ultimately opens new avenues for amplifying cytotoxic CD8+ T cell immunity in the context of next-generation cancer immunotherapies.

Keywords:  adjuvant; cross-presentation/priming; cytotoxic T lymphocytes (CTL); dendritic cells; pimozide

DOI:  https://doi.org/10.3389/fimmu.2026.1946712
Int J Nanomedicine. 2026 ;21 639887

Nanomaterials Reshaping Tumor Metabolism: A New Frontier to Overcome T Cell Exhaustion.

Xiaoyan Zhu, Lin He, Jinwei Li, Shuhui Guo, Xiaoxin Liu, Yongjing Cao, Shaozheng Song.

  Adoptive antitumor immunity ultimately fails because metabolically hostile tumor microenvironments (TME) drive T cells into a dysfunctional exhausted state that current checkpoint blockade only partially reverses. Crucially, the principal metabolic stresses - accumulation of lactate, lipids and adenosine, deprivation of glucose and amino acids, and hypoxia - do not act in isolation but form a densely cross-regulated network that progressively reinforces T cell exhaustion. This review synthesizes how each barrier arises and how they amplify one another, then maps nanomaterial-based countermeasures onto this network: catalytic nanomaterials that degrade lactate and adenosine, lipid-modulating and mitochondria-targeted formulations, amino-acid replenishment systems, and hypoxia-relieving designs that pair metabolic correction with checkpoint inhibition or photodynamic therapy. Particular attention is given to the design principles - tissue targeting, stimuli-responsive release and rational combination - that determine whether metabolic reprogramming yields durable restoration of T cell function rather than transient phenotypic rescue. Emerging preclinical evidence indicates that nanomaterial-mediated metabolic remodeling can convert the immunosuppressive TME into an immune-supportive niche and recover effector function of exhausted T cells. We further identify the key gaps that currently limit clinical translation: the absence of subset-level evaluation distinguishing reversible progenitor-like exhausted T cells from terminally exhausted cells, the lack of epigenetic endpoints such as histone lactylation, off-target metabolic suppression of T cells themselves, and the manufacturing and safety hurdles of clinical-grade nanomaterials. Resolving these issues would establish metabolic reprogramming as a credible frontier for next-generation cancer immunotherapy.

Keywords:  T cell exhaustion; TME; metabolic reprogramming; nanomaterials; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S639887
Cell. 2026 Oct 21. pii: S0092-8674(26)01197-9. [Epub ahead of print]

Proteomic atlas of T cell exhaustion defines proteostatic collapse.

Sydnye L Shuttleworth, Michael A Bauer, Dennis W Province, Jessica L Kelliher, Nicole E Scharping, Alexander Monell, Lora J Rogers, Thomas A Williams, Grant T Dawson, Katherine F Wallis, Duah Alkam, Jacob L Edmondson, Daniel Fil, Aaron J Storey, Anna L Bolding, Rick D Edmondson, Stephanie D Byrum, Karen E Beenken, Samuel G Mackintosh, Ananda W Goldrath, Alan J Tackett, Brian Koss.

  T cell exhaustion limits the success of cancer immunotherapies, yet the proteomic changes underlying this dysfunctional state remain poorly understood. We integrated transcriptomics, quantitative proteomics, turnover proteomics, and ubiquitin proteomics to construct a multi-omic atlas of T cell exhaustion. These studies identified pathways regulated through transcriptional and post-translational mechanisms, including degradative and nondegradative ubiquitin modifications, and uncovered widespread changes in proteostasis, metabolism, and DNA repair. Major shifts were revealed in the ubiquitin-proteasome system, as differential expression of E3 ubiquitin ligases correlates with immunotherapy outcomes. These findings position the collapse of proteostasis as a central, underappreciated feature of T cell exhaustion and reveal opportunities to restore T cell function. We demonstrate that overexpression of the E3 ligase RNF166 enhances T cell persistence in vitro and in vivo. This work defines proteome-turnover dynamics as a critical regulatory layer in progressive T cell dysfunction, with broad implications for advancing cancer immunotherapy through manipulation of E3 ligases.

Keywords:  CAR-T; E3 ubiquitin ligase; T cell; cancer immunotherapy; cell therapy; exhaustion; half-life; protein-turnover dynamics; proteostasis; ubiquitin

DOI:  https://doi.org/10.1016/j.cell.2026.09.051
Front Immunol. 2026 ;17 1940201

Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity.

Keith Alan Nair, Jessica Lee, Olivia Zaleski, Luciano Mazzoccoli, Brian Deng, Chih-Chi Andrew Hu, Stanley Ching-Cheng Huang, Andreas Wieland, Hazem E Ghoneim, Haitao Wen, Xiaopei Huang, Bei Liu.

  CD8+ T cells play a crucial role in anti-tumor immunity; however, their functionality is compromised by exhaustion driven by chronic antigen exposure, poor tumor microenvironment, and metabolic dysfunction. Activated CD8+ T cells undergo extensive proteomic remodeling, which includes the induction of the IRE1-XBP1 signaling axis of the unfolded protein response. However, the functional consequences of sustained IRE1-XBP1 activation in exhausted CD8+ T cells remain elusive. Using a model of constitutive XBP1 activation in CD8+ T cells, we demonstrate that sustained XBP1s signaling leads to reduced homeostatic CD8+ T cell populations, impaired migratory capacity, and dampened anti-tumor immunity. Notably, pharmacological inhibition of the IRE1-XBP1 axis significantly reduces tumor burden through a dual mechanism that targets both tumor cells and the immune compartment. Our findings reveal a previously unappreciated role for XBP1s in regulating CD8+ T cell biology and highlight the IRE1-XBP1 axis as a therapeutic target in solid tumors.

Keywords:  CD8+ T cells; T cell exhaustion; XBP1s; anti-tumor immunity; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2026.1940201
Cell Commun Signal. 2026 Jul 25. pii: 570. [Epub ahead of print]24(1):

ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors.

Shaochun Liu, Jian Xu, Han Zhang, Yuhan Tang, Xiaoxi Han, Wenjing Xiong, Linlin Fan, Chang Su, Zhiqi Sui, Wenhui Zhao.

  The tumor microenvironment (TME) is now understood as an active regulator of therapeutic vulnerability. In this Review, we use an integrative stromal-checkpoint framework, informed by published stromal and fibroblast checkpoint studies, to describe stromal programs that couple extracellular matrix (ECM) remodeling, metabolic stress, vascular dysfunction, and immune exclusion into treatment-resistant tumor ecologies. We focus on a disintegrin and metalloproteinase 12 (ADAM12) because ADAM12-high or ADAM12-positive tumor-stromal states have been linked to collagen-rich desmoplasia, mechanotransduction, hypoxia-associated stress, lactate-associated acidosis, immune-excluded spatial organization, and therapy resistance in solid tumors. Evidence spans fibroblast, mesenchymal stromal-cell, and tumor-cell perturbation studies; mechanistic substrate and signaling analyses; spatial and clinical datasets; and broader tissue-level immune contexts relevant to lymphatic drainage, tumor-draining lymph node (TDLN) priming, tissue-resident immune cells, and ILC2/type 2 immune programs. Across these evidence layers, ADAM12 emerges as an isoform-aware and cell-of-origin-dependent marker, amplifier, and context-dependent candidate target for selected high-barrier tumor states. We discuss how ADAM12-informed biomarkers, spatial barrier profiling, and stromal-priming strategies can support patient stratification and combination-therapy design. Overall, ADAM12-associated biology provides a useful model for examining how stromal resistance may be built, maintained, and therapeutically remodeled in selected tumor contexts.

Keywords:  ADAM12; Extracellular matrix remodeling; Immune exclusion; Stromal-checkpoint framework; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-026-03103-8
Cardiovasc Res. 2026 Oct 22. pii: cvag238. [Epub ahead of print]

Clonal expansion of CD8+ effector T cells in patients with calcific aortic valve disease.

Francesca Bartoli-Leonard, Sarvesh Chelvanambi, Tan Pham, Casandra L Clift, Mandy E Turner, Mark C Blaser, Sasha A Singh, Massimo Caputo, Masanori Aikawa, Amanda Pang, Jochen Muehlschlegel, Elena Aikawa.

AIMS: Calcific aortic valve disease (CAVD) is a complex cardiovascular pathology, culminating in aortic stenosis and heart failure with no effective treatment strategy, except invasive surgery. While inflammation may contribute to valvular fibro-calcific pathology and T cells have been identified within the leaflets, their contribution to CAVD pathogenesis remains unclear.
METHODS & RESULTS: Disease-staged whole-tissue proteomics (n=16) confirmed a pro-inflammatory T cell driven signature, with immunohistochemistry (n=10) and immunofluorescence (n=8) conducted on control and CAVD valves to confirm T cell localization to calcified regions. Flow cytometry immunophenotyping (n=20) was was performed using valvular tissue and corresponding peripheral blood from the same individuals. Single cell RNA sequencing and paired single T cell receptor sequencing was conducted on an additional 4 patients on CD45+, CD3+, CD4+ or CD8+ T cells. T cell signaling was identified through unsupervised clustering. Tissue resident memory (TRM) T cells were detected within the valve, exhibiting a highly cytotoxic, activated, and terminally differentiated phenotype. This pan-pro-inflammatory signal was differentially identified in T cells originating from the valve tissue, and not observed in the blood, indicative of an adaptive, local and non-systemic inflammatory signature in CAVD patients. T cell receptor analysis detected hyperexpanded clones within the CD8+ T cell central memory (TCM) population, with TRM cells comprising most of the large and medium clonal expansion within the T cell population. Clonal expansion was more prominent in valve tissue, with expanded clones largely confined to their tissue of origin. Clonal interaction network analysis demonstrated the greatest proportion of clones originating from CD8+ TCM and TRM populations, exhibiting a tissue resident, cytotoxic environment within the valve.
CONCLUSIONS: Taken together, the data define distinct T cell subpopulations in CAVD and implicate specific antigenic epitopes driving clonal expansion of valvular T cells, supporting a central role for antigen-driven, autoimmune-like inflammation in disease propagation.

DOI: https://doi.org/10.1093/cvr/cvag238
Cancer Lett. 2026 Oct 18. pii: S0304-3835(26)00672-5. [Epub ahead of print]661 218908

Tumor endothelial cells as vascular immune gatekeepers: reprogramming the vascular-immune interface for cancer immunotherapy.

Tianming Zhang, Chu Zhang, Chao Wang, Mingzhong Sun, Jianming Wei, Jian Yu, Linlin Sui, Wenxue Ma.

  Despite durable clinical responses to immunotherapy in a subset of patients, most solid tumors remain refractory owing to an immune-excluded phenotype characterized by limited trafficking, infiltration, and function of effector immune cells within the tumor microenvironment (TME). Tumor endothelial cells (TECs) function as vascular immune gatekeepers that orchestrate this process. Driven by persistent pro-angiogenic signaling and metabolic stress, TECs establish a multilayered immune barrier through structurally abnormal, poorly perfused vasculature, endothelial anergy, and active immunosuppressive programs. TECs directly suppress effector T-cell and natural killer (NK)-cell function through checkpoint-like ligands, death-ligand pathways, and immunometabolic mechanisms involving adenosine production and tryptophan catabolism. Simultaneously, they recruit, retain, and reprogram immunosuppressive leukocytes, thereby reinforcing immune exclusion and therapeutic resistance. Here, we propose a TEC-centric vascular immune gatekeeping framework and review strategies to reprogram tumor vessels from immune barriers into conduits for effective immune-cell trafficking and activation. We discuss endothelial-directed monotherapies that transiently normalize or reset TEC states, together with combination strategies integrating vascular modulation with immune checkpoint blockade, adoptive and innate immune-cell therapies, cancer vaccines, oncolytic viruses, STING agonists, and multifunctional antibodies. We also highlight key translational considerations, including biomarker-guided patient stratification, pharmacodynamic monitoring using mechanism-based endpoints, and optimization of treatment dose and scheduling within the vascular normalization window. Overall, this review establishes endothelial reprogramming as a central strategy for overcoming vascular immune gatekeeping and provides a mechanistic framework for biomarker-guided vascular-immune combination therapies in solid tumors.

Keywords:  Cancer immunotherapy; Endothelial anergy; Endothelial reprogramming; Tumor endothelial cells; Vascular immune gatekeeping

DOI:  https://doi.org/10.1016/j.canlet.2026.218908