bims-tuinly 2026-03-22 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–03–22
thirty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Phase I trial of locoregional administration of autologous tumor-infiltrating lymphocytes in patients with uveal melanoma and liver metastases (the HAITILS trial).
The Correlation Between CD8+ Tumor-Infiltrating Lymphocytes and the Efficacy of Neoadjuvant Therapy in Breast Cancer.
Tumor-infiltrating lymphocyte therapy in triple-negative breast cancer: from mechanistic exploration to clinical translation.
Combinatorial immunotherapy drives exhaustion in tumor antigen-specific CD8+ T cells within the mouse renal tumor microenvironment.
Locoregional recurrence of triple-negative breast cancer with low tumor-infiltrating lymphocytes: a case report.
Next-generation immune cell therapies for lung cancer: advances in CAR-T, NK, and TIL strategies.
Driving CAR therapies beyond T cells.
Mismatch Repair Proteins and CD45RO-Positive Lymphocytes in Malignant and Benign Salivary Gland Tumors: A Favorable Association with Disease Clinical Parameters.
CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance.
Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice.
Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy.
Efficacy and safety of approved cellular therapies and bispecific antibodies in solid tumors: the current state.
Immunity, age, and luminal breast cancer: understanding the Holy Trinity.
T-cell receptor-engineered T cells (TCR-e T cells): A novel cellular therapy for hematopoietic malignancies?
Associations Between Pigmentation and the Clinicopathologic and Immune Landscape of Melanoma.
The cost-effectiveness of tumour-infiltrating lymphocyte cell therapy for advanced melanoma: a systematic review.
KLRG1 defines a distinct tumor-infiltrating granzyme K+ CD8 + T cell population.
Albumin-Bound STING Agonist Reprograms HSPCs to Antitumor Neutrophils Enhancing CD8+ T Cell Immunity.
CD27 expression is a clinically accessible biomarker for predicting immunotherapy response in melanoma.
[Metallophilic macrophages of the splenic marginal zone: myeloid sentinels capable of cross-priming CD8+ T cell antitumor immunity].
The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.
CD8+ T Cell Infiltration Elicits Molecular Subtype-Biased Clinical Outcomes in Gastric Cancer Patients.
Sequential personalized neoantigen vaccination following first-line treatments demonstrates safety and efficacy in advanced hepatocellular carcinoma.
IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer.
FOXM1-specific TCR-engineered T cells target non-small cell lung cancer.
B cell depletion promotes melanoma tumor growth in a CD4+ T cell-dependent manner.
Regulation of the immune CD155-CD226-TIGIT axis by cyclin D-CDK4/6.
T cell-intrinsic VISTA expression promotes resistance to CTLA-4 blockade by restricting CD8+ T cell responses.
Sustained nitric oxide production by engineered E. coli remodels the tumor microenvironment and potentiates immunotherapy.
Endogenous glucocorticoids and glucocorticoid receptor signaling: Dual regulators of PD-1/PD-L1 immunotherapy efficacy in the tumor microenvironment.

J Immunother Cancer. 2026 Mar 18. pii: e014401. [Epub ahead of print]14(3):

Phase I trial of locoregional administration of autologous tumor-infiltrating lymphocytes in patients with uveal melanoma and liver metastases (the HAITILS trial).

Axel Nelson, Rebecca Riise, Samuel Alsén, Andrew Wong, Per Carlson, Sebastian Edman, Jan Holgersson, Roger Olofsson Bagge, Iva Johansson, May Sadik, Lars Edenbrandt, Lisa M Nilsson, Jonas A Nilsson, Lars Ny.

   BACKGROUND: Uveal melanoma is a rare melanoma subtype characterized by a liver-dominant pattern of metastasis which is associated with a lack of durable responses to immunotherapies. Adoptive cell transfer of autologous tumor-infiltrating lymphocytes (TILs) has been shown to induce responses in a subset of patients with metastatic uveal melanoma. The safety and feasibility of locoregional administration of TIL therapy via hepatic arterial infusion (HAI) have not previously been evaluated.
PATIENTS AND METHODS: This prospective, open-label, phase I trial investigated the safety and feasibility of one-time TIL therapy administered via HAI in patients with liver metastases of uveal melanoma. Preconditioning chemotherapy with melphalan (1 mg/kg, intravenous) was administered on day -5. TILs were delivered via percutaneous catheterization of the hepatic artery according to a dose escalation scheme (0.1, 0.3, or 1×109 cells) on day 0. Patients received daily subcutaneous interleukin-2 (IL-2, 2 MIU) up to 14 days after TIL administration. The primary endpoint was the incidence and severity of adverse events (AEs). Secondary endpoints included clinical efficacy and the feasibility of TIL production using a semiautomated manufacturing system.
RESULTS: Six patients received TIL therapy manufactured using the CliniMACS Prodigy platform; five were treated according to protocol, while one received a lower TIL dose than planned. All had received prior systemic treatment. No AEs related to the HAI procedure were observed. All patients experienced grade ≥3 hematologic AEs related to preconditioning chemotherapy, and two patients experienced grade ≥3 AEs attributed to TIL/IL-2. Best overall response was stable disease in all patients (100%). Median progression-free survival was 4 months, and median overall survival was 14 months.
CONCLUSIONS: TILs can be manufactured using the CliniMACS Prodigy. Administration of TIL via HAI was safe and feasible in patients with liver-dominant metastatic uveal melanoma. The used regimen appears insufficient to achieve durable clinical efficacy and implies a need for further testing to obtain conclusive results.
TRIAL REGISTRATION NUMBERS: NCT04812470, EUCT number: 2024-512877-28-00, EudraCT number: 2020-006126-31.

Keywords:  Adoptive cell therapy - ACT; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2025-014401
Breast Cancer (Dove Med Press). 2026 ;18 533799

The Correlation Between CD8+ Tumor-Infiltrating Lymphocytes and the Efficacy of Neoadjuvant Therapy in Breast Cancer.

Guosheng Feng, Mingqiang Zhong, Danmin Xie, Xianbin Yuan, Shui Lu, Jianfang Zhu, Shan Gao, Zhongqiu Yi, Haiyong Lin, Jinlin Zheng, Hongyu Zhou, Yanjing Wang.

   Objective: This study aims to investigate the correlation between the CD8+ tumor-infiltrating lymphocytes (TILs) expression and the efficacy of neoadjuvant therapy (NAT) in breast cancer, while previous studies have reported inconsistent findings regarding the predictive value of CD8+ TILs.
Methods: Data from 94 breast cancer patients who underwent NAT between January 2017 and June 2019 were retrospectively analyzed. Preoperative CD8+ TILs expression was evaluated through immunohistochemistry, and its association with clinical and pathological responses to NAT was assessed.
Results: Univariate analysis indicated that tumor stage, axillary lymph node status, and intratumoral CD8+ TILs were correlated with clinical complete response (cCR). Multivariate analysis identified intratumoral CD8+ TILs as an independent predictor of cCR (OR 3.038; p=0.02). Patients achieving pathological complete response (pCR) exhibited significantly higher intratumoral CD8+ TILs expression compared to those without (p=0.04). Univariate analysis also linked estrogen receptor (ER), progesterone receptor (PR), HER2 status, and intratumoral CD8+ TILs to pCR, with multivariate analysis confirming intratumoral CD8+ TILs as an independent predictor (OR 4.036; p=0.02).
Conclusion: Our findings suggest that intratumoral CD8+ TILs are an independent predictor of the efficacy of neoadjuvant therapy in breast cancer. In the future, incorporating intratumoral CD8+ TILs into existing clinicopathological predictive models and combining their assessment with other immune biomarkers may enable the development of more robust predictive tools, thereby providing a solid foundation for truly individualized and precision-based neoadjuvant treatment in breast cancer.

Keywords:  Breast cancer; CD8+ TILs; Efficacy prediction; Neoadjuvant therapy; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.2147/BCTT.S533799
Front Immunol. 2026 ;17 1741333

Tumor-infiltrating lymphocyte therapy in triple-negative breast cancer: from mechanistic exploration to clinical translation.

Yongxi Wang, Zhe Zhang, Zhuo Chen, Xiaoyun Xie, Fang Wang.

  Breast cancer is a common malignancy among women, with triple-negative breast cancer (TNBC) representing a subtype with poor prognosis. Due to the lack of expression of targetable receptors, traditional hormone therapy and HER2-targeted therapy are ineffective against TNBC. Moreover, TNBC typically exhibits more aggressive biological behavior, with a high propensity for recurrence and metastasis, further exacerbating its poor prognosis. While chemotherapy remains the primary treatment modality, its efficacy is limited, and patients readily develop resistance. Consequently, exploring novel therapeutic strategies and targets is crucial for improving the prognosis of patients with TNBC. Tumor-infiltrating lymphocytes (TILs) are promising prognostic and predictive biomarkers of TNBC. Multiple studies have demonstrated that a higher number of TILs in early-stage TNBC is correlated with favorable outcomes. Furthermore, clinical trials have demonstrated that TIL therapy is effective in solid tumors. This review outlines the current understanding of the TIL role in TNBC, elucidates the mechanisms and clinical efficacy of TIL therapy, and discusses future research directions and challenges for TILs.

Keywords:  TIL therapy; TILs; TNBC; immunotherapy; predictive biomarkers

DOI:  https://doi.org/10.3389/fimmu.2026.1741333
J Immunol. 2026 Mar 17. pii: vkag013. [Epub ahead of print]215(3):

Combinatorial immunotherapy drives exhaustion in tumor antigen-specific CD8+ T cells within the mouse renal tumor microenvironment.

Holly R Stephens, Elizabeth Elkins, Jing Li, Zoey N Swalley, Henry Nnaemeka Ogbonna, Pia Muri, Zachary Roberts, Francesca R Dempsey, Md Akkas Ali, Md Hasanul Banna Siam, Richard Kirkman, Jianqing Zhang, Sunil Sudarshan, Daniel J Tyrrell, Hubert M Tse, Daniel L Smith, Lyse A Norian.

  Immunotherapies have greatly improved outcomes for patients with renal cell carcinoma (RCC), yet response rates remain suboptimal and the factors promoting therapy resistance versus sensitivity are incompletely understood. Currently, no preclinical model of orthotopic renal cancer exists that permits evaluation of tumor antigen-specific (TAS) CD8+ tumor-infiltrating lymphocytes (TILs). To address this deficiency, we developed a mouse renal cancer model that permits tracking of adoptively transferred TAS CD8+ T cells. Renca-LUC tumor cells were transduced to express tumor ERK (tERK), a model antigen expressing a one-amino-acid change from wild-type ERK, resulting in recognition by tERK/H-2Kd-specific DUC Thy1.1 TCR transgenic CD8+ T cells. Renca-tERK-LUC challenge into DUC Thy1.1 mice results in rapid tumor clearance. To assess intratumoral TAS T-cell responses, we adoptively transferred limited numbers of DUC Thy1.1 T cells into mice with established renal tumors, followed by clinically relevant anti-PD-1 + anti-VEGFR-2 combinatorial immunotherapy. We used standard flow cytometry gating as well as unbiased Leiden clustering of stained cells to assess TIL phenotypes and prevalence. Therapy responders showed intratumoral gene expression changes reflective of those seen in human RCC responders to therapy, and had increased frequencies of activated and exhausted CD8+ TILs, activated CD4+ TILs, and NKp46+ natural killer cells. Examination of CD8+ TILs revealed unique aspects of the TAS response characterized by reduced phenotypic cluster heterogeneity and heightened levels of PD-1+CD39+CD44+CD8+ TILs versus endogenous CD8+ TILs from the same tumors. Future studies using this model should yield insights into the biology of TAS CD8+ TILs in renal tumors and facilitate the development of novel immunotherapies for patients with RCC.

Keywords:  T cells; cancer; cytotoxic; transgenic/knockout mice; tumor immunity

DOI:  https://doi.org/10.1093/jimmun/vkag013
Pan Afr Med J. 2025 ;52 161

Locoregional recurrence of triple-negative breast cancer with low tumor-infiltrating lymphocytes: a case report.

Khadija Khadiri, Zineb Khadrouf, Malak Sadry, Amina Essalihi, Oumaima Bouchra, Majda Taoudi Benchekroun, Mehdi Karkouri.

  Triple-negative breast cancer (TNBC) is an aggressive subtype with high histological grade and an increased propensity for early recurrence. Early locoregional recurrence within three months of a Patey mastectomy is uncommon, making this case noteworthy and contributing valuable insight into the biological aggressiveness of TNBC and the prognostic role of tumor-infiltrating lymphocytes (TILs). We report the case of a 49-year-old postmenopausal woman followed for TNBC at the Mohammed VI Oncology Center in Casablanca, Morocco, who presented with a rapidly enlarging inflammatory mass along the outer edge of the left Patey mastectomy scar, extending toward the axillary tail, three months after surgery. Histopathological evaluation confirmed a locoregional recurrence of invasive carcinoma of no special type, revealing a 12.2 cm grade III tumor with a Ki-67 index of 40%, hormone receptor-negative/HER2-negative status, and low TILs (10%). The patient received neoadjuvant chemotherapy, followed by surgical excision of the recurrent lesion, radiotherapy and adjuvant chemotherapy consisting of capecitabine, vinorelbine, and gemcitabine, with good tolerance and no evidence of distant metastasis during follow-up. This case underscores the prognostic impact of low TILs and highlights the importance of considering the tumor microenvironment in risk stratification and personalized management of TNBC.

Keywords:  Triple-negative breast cancer; case report; locoregional recurrence; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.11604/pamj.2025.52.161.50434
Front Med (Lausanne). 2026 ;13 1787086

Next-generation immune cell therapies for lung cancer: advances in CAR-T, NK, and TIL strategies.

Anoud Khan, Amina Mujahid, Aryan Tareen, Ahrar Amin, Saqib Raza Khan, Danial Khan Hadi, Afsheen Raza.

  Lung cancer remains the leading cause of cancer-related mortality worldwide, and current therapies offer limited survival benefit for patients with advanced disease. While immune checkpoint inhibitors and targeted therapies have improved outcomes in some populations, most patients either fail to respond or develop acquired resistance, highlighting the need for more potent and durable immunotherapeutic strategies. Next-generation immune cell therapies, including chimeric antigen receptor T cells (CAR T), chimeric antigen receptor natural killer cells (CAR NK), and tumor-infiltrating lymphocytes (TIL), provide a promising approach for lung cancers that are refractory to conventional treatment. These therapies leverage the patient's own immune system or engineered immune cells to directly recognize and eliminate malignant cells, while potentially overcoming immunosuppressive tumor microenvironments. This review provides a comprehensive synthesis of recent advances in the design, engineering, and clinical development of CAR T, CAR NK, and TIL therapies in both non-small cell and small cell lung cancer. We discuss preclinical and early clinical studies demonstrating feasibility, safety, and mechanisms of action, including antigen targeting, immune cell persistence, trafficking, and intratumoral activity. Key challenges, such as tumor antigen heterogeneity, immune suppression, limited durability, and off-tumor toxicity, are critically evaluated. We also examine emerging strategies to enhance efficacy, including multi-antigen targeting, armored and logic-gated constructs, regional delivery, combination with checkpoint inhibition or other modulators, and scalable off-the-shelf manufacturing platforms. Collectively, these next-generation immune cell therapies represent a rapidly evolving and translationally relevant approach that may expand therapeutic options, improve survival, and provide durable antitumor responses in patients with lung cancer who have exhausted conventional therapies.

Keywords:  chimeric antigen receptor T cells; chimeric antigen receptor natural killer cells; lung cancer; next generation immune cell therapies; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fmed.2026.1787086
Trends Cancer. 2026 Mar 18. pii: S2405-8033(26)00039-7. [Epub ahead of print]

Driving CAR therapies beyond T cells.

Cecilie Ø Madsen, Thomas M Hulen, Maria Ormhøj, Sine R Hadrup, Inge M Svane, Özcan Met.

  Chimeric antigen receptor (CAR)-T cell therapy has reshaped cancer immunotherapy for hematological malignancies, yet progress in solid tumors remains limited. Physical barriers, antigen heterogeneity, and immunosuppressive tumor microenvironment restrict the activity and persistence of CAR-T cells, while safety concerns complicate target selection. Extending CAR technology to alternative immune lineages, such as macrophages, natural killer cells, tumor-infiltrating lymphocytes, and unconventional T cells, offers complementary mechanisms for tumor recognition, infiltration, and immune modulation. This review highlights recent advances in these emerging CAR platforms, compares their biological and translational features, and outlines how integrating cell-intrinsic properties with CAR design may guide the next generation of cellular immunotherapies for solid tumors.

Keywords:  CAR-T therapy; NK cells; macrophages; tumor-infiltrating lymphocytes; unconventional T cells

DOI:  https://doi.org/10.1016/j.trecan.2026.02.008
Int Arch Otorhinolaryngol. 2026 Jan;30(1): 1-9

Mismatch Repair Proteins and CD45RO-Positive Lymphocytes in Malignant and Benign Salivary Gland Tumors: A Favorable Association with Disease Clinical Parameters.

Hamid Ghaderi, Yousef Mohammadi, Simin Ahmadvand, Akbar Safaei, Sajjad Gerdabi, Fatemeh Asadian, Bijan Khademi, Mohammad Reza Haghshenas, Abbas Ghaderi.

   Introduction: Salivary gland tumors (SGTs) are uncommon lesions that account for 3 to 6% of head and neck cancers.
Objective: To investigate mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and CD45RO expression in salivary gland tumors (SGTs).
Methods: Proteins MLH1, MSH2, MSH6, and PMS2 of the MMR proteins family and CD45RO were evaluated using immunohistochemistry (IHC). Hematoxylin and eosin-stained sections were scored to explore the rate of TILs.
Results: None of the malignant and benign SGTs had partial or complete loss of at least one of the MMR proteins. Mucoepidermoid carcinomas, adenoid cystic carcinomas, salivary ductal carcinomas, and acinic cell carcinomas as malignant tumor types, and pleomorphic adenoma and Warthin's tumors as the most common benign tumors showed considerable differences in terms of the infiltration of TILs and CD45RO. Malignant tumors exhibited a notable difference in the infiltration of CD45RO + cells compared to benign ones. Both the tumor, node, metastasis (TNM) stage and the histological grade were shown to be linked with the infiltration status of CD45RO + cells.
Conclusion: Our results show that MMR deficiency might be insignificant and less relevant in SGTs. However, differences in TIL rate and CD45RO expression indicate that each of the SGT tumor types may have distinguished immune microenvironments. Malignant SGTs have higher infiltration of activated immune cells, and, thereby, these cells can be considered as good indicators of patient's status.

Keywords:   CD45RO + memory cells ; mismatch repair proteins; salivary gland tumors; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1055/s-0045-1806721
J Nanobiotechnology. 2026 Mar 14.

CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance.

Zhou Jiang, Yuning Li.

  Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, and the limited efficacy of immunotherapy due to treatment resistance underscores the urgent need for new therapeutic strategies. In the present study, CD93-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating resveratrol (CD93-NPs@RSV) were developed to remodel the metabolic fitness of CD8+ tumor-infiltrating lymphocytes. The nanoparticles were precisely engineered and characterized using dynamic light scattering, transmission electron microscopy, and in vivo imaging, which confirmed their stability and tumor-targeting capability. Mechanistic studies revealed that CD93-NPs@RSV suppressed CD93 expression, facilitated apoptosis-inducing factor (AIF) mitochondrial translocation, and activated oxidative phosphorylation (OXPHOS), thereby enhancing T cell function in the tumor microenvironment. Transcriptomic and proteomic analyses further confirmed regulation of the CD93-AKT-PAK5-AIF signaling axis. In a Lewis LC model, CD93-NPs@RSV significantly inhibited tumor progression and displayed strong synergy with anti-PD-1 therapy, resulting in improved survival outcomes. Collectively, our study demonstrates that CD93-NPs@RSV provide a powerful nanotechnology-driven approach to reverse immunotherapy resistance by reprogramming T cell metabolism. These findings establish a promising paradigm for precision cancer immunotherapy and underscore the translational potential of targeted nanomedicine in overcoming therapeutic bottlenecks in LC.

Keywords:  CD93-targeted nanoparticles; Lung cancer immunotherapy resistance; Mitochondrial metabolic reprogramming; Oxidative phosphorylation; Resveratrol

DOI:  https://doi.org/10.1186/s12951-026-04216-5
Nat Commun. 2026 Mar 17.

Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice.

Xuhao Zhang, Yu Gao, Wenbo Hu, Yong Liang, Xiaozhe Yin, Xiangjun Shi, Hongjia Li, Huiping Liao, Jingya Guo, Xiaohong Yu, Mingzhao Zhu, Hua Peng, Wenyan Wang, Yang-Xin Fu.

Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3+TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFNα-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFNα and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.

DOI: https://doi.org/10.1038/s41467-026-70876-4
Nat Biomed Eng. 2026 Mar 17.

Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy.

Yan-Ruide Li, Haochen Nan, Zeyang Liu, Ying Fang, Yichen Zhu, Zibai Lyu, Zhengyao Shao, Enbo Zhu, Bo Zhang, Youcheng Yang, Xinyuan Shen, Yuning Chen, Tzung Hsiai, Lili Yang, Song Li.

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes with allogeneic potential and strong solid tumour-homing capacity, making them attractive for cancer immunotherapy. Unlike conventional T cells, iNKT cells recognize lipid antigens presented by the non-polymorphic CD1d molecule. Chimaeric antigen receptor (CAR)-redirected iNKT (CAR-iNKT) cells have shown promise; however, their clinical efficacy is limited by insufficient activation and poor long-term persistence within the tumour microenvironment. Here we describe the iNKT cell-targeted microparticle recruitment and activation system (iMRAS), a biomimetic platform engineered to locally recruit, activate and expand CAR-iNKT cells in vivo. Acting as an in vivo 'charging station', iMRAS provides chemotactic and activating cues that enhance CAR-iNKT cell functionality, improving persistence and tumour control in preclinical lymphoma and melanoma models. Through its biomimetic design and localized immunostimulatory effects, iMRAS helps overcome the limitations of current therapies for solid tumours, establishing a robust platform for advancing CAR-iNKT cell-based cancer immunotherapy.

DOI: https://doi.org/10.1038/s41551-026-01629-3
Discov Oncol. 2026 Mar 17.

Efficacy and safety of approved cellular therapies and bispecific antibodies in solid tumors: the current state.

Rabab Zehra Jafry, Saba Bilal Qamar, Sohaib Irfan, Muhammad Abbas Abid, Virginia Mohlere, Neha Maithel, Syed Hassan Jafri, Sanjay Awasthi, Samer Srour, Irfan A Vaziri, Muhammad Bilal Abid.



Keywords:  Bispecific antibodies; Efficacy; Lung cancer; Metastatic melanoma; Safety; Synovial sarcoma; T-cell receptor therapy; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s12672-026-04802-x
Clin Cancer Res. 2026 Mar 19.

Immunity, age, and luminal breast cancer: understanding the Holy Trinity.

Roberto Salgado, Marleen Kok.

In 390 patients with stage I-III hormone-receptor positive/HER2-negative breast tumors higher number of Tumor Infiltrating Lymphocytes (TILs)-subtypes, regardless of whether they were immunostimulatory or immunosuppressive, including T-regulatory cells and CD8- and non-CD8 T-cells, are associated with improved distant disease free survival and overall survival at 8 years follow-up.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4035
Transpl Immunol. 2026 Mar 18. pii: S0966-3274(26)00040-7. [Epub ahead of print] 102382

T-cell receptor-engineered T cells (TCR-e T cells): A novel cellular therapy for hematopoietic malignancies?

Kajetan Karaszewski, Wiesław Wiktor Jędrzejczak.

  Despite the undeniable successes of chimeric antigen receptor T cells in the treatment of numerous hematopoietic malignancies, instances in which this therapy shows limited effectiveness, such as in acute myeloid leukemia (AML), still exists. This situation has prompted a search for alternative cellular therapies for neoplastic diseases. T-cell receptor-engineered T cells (TCR-e T cells) represent another approach to cellular cancer therapy that relies on the genetic modifications of lymphocytes. They are designed to interact with endoplasmic tumor-associated antigens (TAAs) presented on the cell surface via the major histocompatibility complex. Hence, the therapeutic effect is restricted to individuals with a specific TAA overexpression in the context of particular human leukocyte antigen types. Although promising results and the first approvals of TCR-e T cells for the treatment of solid tumors have been reported, only a few phase I/II clinical trials have been registered in hematopoietic malignancies, and some were terminated before yielding conclusive results. The most investigated TAAs as targets for TCR-e T cells in hematopoietic malignancies include Wilms tumor 1 (WT1), preferentially expressed antigen in melanoma (PRAME), and minor histocompatibility antigen (MiHA) in patients with AML. Similarly, New York esophageal squamous carcinoma 1 (NY-ESO-1) and B-cell-specific coactivator OBF-1 (BOB1) markers have been targeted in patients with multiple myeloma. With promising preliminary results, TCR-e T cell therapies targeting WT1, PRAME, MiHA, NY-ESO-1, and BOB1 remain under development as therapeutic options for hematologic malignancies.

Keywords:  Acute myeloid leukemia; Cellular therapy; Hematology; Multiple myeloma; TCR engineered T cells

DOI:  https://doi.org/10.1016/j.trim.2026.102382
Am J Dermatopathol. 2026 Mar 20.

Associations Between Pigmentation and the Clinicopathologic and Immune Landscape of Melanoma.

Helana Ghali, Ayah N Al-Bzour, Aleena Boby, Shaliz Aflatooni, Danielle K DePalo, Michelle M Dugan, Emily Coughlin, Rahul Mhaskar, Kenneth Tsai, Jonathan S Zager, Vernon K Sondak, Sanjay Premi, Walter J Storkus, Jane L Messina, Lilit Karapetyan.

   ABSTRACT: Pigmentation varies widely in cutaneous melanoma, but its clinicopathologic and immunologic implications are incompletely defined. We retrospectively reviewed 627 patients with stage II-III melanoma treated at H. Lee Moffitt Cancer Center (2010-2019) and correlated pathologist-graded tumor pigmentation (0-3) with tumor features and sentinel lymph node biopsy results. We then evaluated transcript levels of pigmentation markers (TYR, DCT, MITF) for associations with overall survival (OS), tumor microenvironment (TME) composition, and immune checkpoint inhibitor (ICI) response using TCGA-SKCM bulk RNA-seq (n = 443) and public cohorts (GSE91061, GSE115978, GSE120575). Pigmented tumors (74.2%) showed lower Breslow depth (P = 0.001), more tumor-infiltrating lymphocytes (P < 0.001), greater angiolymphatic invasion (P = 0.03), enrichment for superficial spreading subtype (P < 0.001), and higher sentinel lymph node biopsy positivity (P < 0.05) versus nonpigmented tumors. In TCGA, high TYR, DCT, and MITF expression independently correlated with worse OS. xCell analysis showed that low expression groups were enriched for multiple effector T- and B-cell populations, whereas high expression associated with immunosuppressive cell types (e.g., M2 macrophages, Tregs). In an ICI-treated cohort (GSE91061), baseline MITF was higher in nonresponders (P = 0.023). Single-cell analyses confirmed pigmentation gene expression in malignant cells and demonstrated elevated MITF within myeloid subsets of nonresponders. Overall, both histologic pigmentation and pigmentation-gene signatures associate with tumor characteristics, immune contexture, and clinical outcomes, suggesting potential utility for risk stratification and treatment response prediction.

Keywords:  immune checkpoint inhibitors; melanoma; pigmentation; tumor microenvironment; tyrosinase

DOI:  https://doi.org/10.1097/DAD.0000000000003223
BMC Cancer. 2026 Mar 20.

The cost-effectiveness of tumour-infiltrating lymphocyte cell therapy for advanced melanoma: a systematic review.

Mengjun Wu, James Larkin, Andrew Furness, Charitini Stavropoulou.



Keywords:  Advanced melanoma; Economic evaluation; Standard treatment; Systematic review; Tumour-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s12885-026-15888-5
J Cancer Res Clin Oncol. 2026 Mar 19. pii: 71. [Epub ahead of print]152(3):

KLRG1 defines a distinct tumor-infiltrating granzyme K+ CD8 + T cell population.

Jerin Thomas, Sophia Kennedy, Stella Darcy, Henrique Malaco, Nyasha Chambwe, Dev Kamdar, Lucio Periera, Andrew Salama, Danielle Scarola, Brett Miles, Douglas Frank, Nagashree Seetharamu, Rajarsi Mandal.



Keywords:  Granzyme K; Head and neck cancer; Immunotherapy; Single cell RNA sequencing; Tumor infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s00432-026-06450-8
Adv Sci (Weinh). 2026 Mar 19. e23603

Albumin-Bound STING Agonist Reprograms HSPCs to Antitumor Neutrophils Enhancing CD8+ T Cell Immunity.

Jinsong Tao, Hong-Yi Zhao, Chengyi Li, Hanning Wen, Fang Ke, Qiuxia Li, Miao He, Bo Wen, Zhongwei Liu, Kai Sun, Wei Gao, Duxin Sun.

  Tumor-associated immunosuppressive neutrophils, termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), compromise cancer immunotherapy. Emerging evidence indicates that neutrophil fate can be programmed as early as the hematopoietic stem and progenitor cell (HSPC) stage. Reprogramming HSPCs toward antitumor neutrophils offers a promising therapeutic strategy. Here, we demonstrate that an albumin-bound STING agonist (Nano ZSA-51D) reprograms HSPCs to generate antitumor neutrophils, enhancing MHC I-mediated CD8+ T cell immunity and sensitizing tumors to α-PD1 immunotherapy. Nano ZSA-51D expands HSPCs and reprograms them toward granulocyte-monocyte progenitors for neutrophil development. It further converts immature (CD101-) and mature (CD101+) neutrophils into a CD14+ICAM-1+ subset through STING-NF-κB-TNF-α signaling, enhancing tumor infiltration and antitumor activity. These neutrophils upregulate interferon signaling and MHC I antigen presentation, thereby boosting tumor-specific CD8+ T cell responses. Notably, both adoptive transfer of Nano ZSA-51D-reprogrammed neutrophils and systemic Nano ZSA-51D treatment synergizes with α-PD1 therapy to achieve complete remission of colon tumors through neutrophil- and CD8+ T cell-dependent mechanisms, with potent efficacy also validated in otherwise immune-resistant pancreatic cancer models. Our findings establish a therapeutic strategy to reprogram HSPCs toward antitumor neutrophils, highlighting the potential of targeting early hematopoiesis to rewire neutrophil fate in cancer immunotherapy.

Keywords:  CD8+ T cell immunity; STING agonist; antigen presentation; antitumor neutrophils; cancer immunotherapy; hematopoietic stem and progenitor cells

DOI:  https://doi.org/10.1002/advs.202523603
NPJ Precis Oncol. 2026 Mar 14.

CD27 expression is a clinically accessible biomarker for predicting immunotherapy response in melanoma.

Peiyi Xia, Huan Yang, Pu Yu, Yu Miao, Longfei Tang, Yuqiang Wang, Binghui Li, Zeyuan Wang, Guozhong Jiang, Kuisheng Chen, Shenglei Li, Minglei Yang.

Immunotherapy has transformed melanoma treatment, yet only a subset of patients benefit and clinically effective biomarkers remain limited. Here, we report a comprehensive analysis evaluating CD27 as a predictive and prognostic biomarker in melanoma across public datasets and a clinical cohort. Public transcriptomic datasets revealed that high CD27 mRNA expression correlates with immune checkpoint genes, enhanced immune infiltration, and favorable prognosis. In advanced melanoma patients treated with immune checkpoint inhibitors, CD27 demonstrated strong predictive performance based on receiver operating characteristic (ROC) curve analysis, with AUC values of 0.763 (PRJEB23709, n = 91) and 0.659 (GSE91061, n = 51). These findings were validated in a retrospective melanoma cohort (n = 102) from the First Affiliated Hospital of Zhengzhou University. CD27 mRNA levels measured by qRT-PCR achieved an AUC of 0.688, and protein levels assessed by immunohistochemistry yielded an AUC of 0.656, both surpassing PD-L1 (AUC = 0.460). Notably, CD27 IHC showed 69.8% sensitivity compared to 27.9% for PD-L1 in identifying responders. Patients with CD27-positive tumors exhibited significantly longer progression-free survival. Multiplex immunofluorescence confirmed CD27 expression in CD45RO⁺ memory T cells, highlighting its role in mediating anti-tumor immunity. These results establish CD27 as a clinically actionable biomarker with superior predictive value over PD-L1 for melanoma immunotherapy response.

DOI: https://doi.org/10.1038/s41698-026-01374-5
Med Sci (Paris). 2026 Mar;42(3): 248-250

[Metallophilic macrophages of the splenic marginal zone: myeloid sentinels capable of cross-priming CD8+ T cell antitumor immunity].

François-Xavier Mauvais, Peter van Endert.

DOI: https://doi.org/10.1051/medsci/2026029
Pathol Res Pract. 2026 Mar 09. pii: S0344-0338(26)00094-4. [Epub ahead of print]282 156443

The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.

Amirhossein Faghih Ojaroodi, Samin Shokravi, Shabnam Eskandarzadeh, Armin Ghahremanzadeh, Fatemeh Alizadeh, Farinaz Amirikar, Golnaz Mobayen, Danial Mahrooghi, Masoud Lahouty, Karim Shamsasenjan, Mehdi Talebi.

  Tumor-induced hypoxia remains a pivotal characteristic of the tumor microenvironment (TME), significantly impacting immune cell functionality by fostering immunosuppression, tumor advancement, and resistance to therapies. This review consolidates established and emerging insights into how hypoxia, chiefly orchestrated by hypoxia-inducible factors (HIFs), metabolically and functionally reprograms key immune populations such as B cells, CD4 + T-cells, CD8 + T-cells, natural killer (NK) cells, regulatory T-cells (Tregs), and macrophages. We examine hypoxia-driven metabolic adaptations, signaling alterations, and evasion strategies, including enhanced glycolysis, lactate accumulation, and immune checkpoint upregulation. Furthermore, we integrate cutting-edge findings, such as hypoxia's modulation of NK cell cytotoxicity, immune metabolic reprogramming in the TME, HIF-mediated immune modulation, effector T-cell transcriptomic shifts akin to non-responsive tumor-infiltrating lymphocytes, and autophagy-dependent MHC-I suppression for immune evasion. These advancements underscore therapeutic opportunities in targeting hypoxia to bolster antitumor immunity and mitigate immunotherapy resistance in cancer.

Keywords:  Anti-tumor response; HIF signaling; Hypoxia; Immunomodulation; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2026.156443
Cancer Sci. 2026 Mar 20.

CD8+ T Cell Infiltration Elicits Molecular Subtype-Biased Clinical Outcomes in Gastric Cancer Patients.

Zhen Ling, Jieti Wang, Yun Gu, Ziqiu Zhang, Fei Shao, Chao Lin, Hongyong He, Ruochen Li, Hao Liu, Jiejie Xu.

  CD8+ T cell infiltration is essential for antitumor immunity across cancers while its clinical significance in gastric cancer (GC) remains unclear. This reflects molecular heterogeneity of GC, as defined by The Cancer Genome Atlas (TCGA) into four subtypes: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomically stable (GS), each with distinct immune features. We aimed to characterize distribution, clinical relevance, and immune associations of CD8+ T cell infiltration within this molecular framework. TCGA (n = 336) and Zhongshan Hospital (ZSHS, n = 455) cohorts were analyzed. CD8+ T cell infiltration and immune features were compared across TCGA subtypes. Prognostic and predictive significance of CD8+ T cells was evaluated in ZSHS cohort. CD8+ T cell infiltration was elevated in the EBV-positive and MSI subtypes (ZSHS: p = 0.026; TCGA: p < 0.001). In ZSHS cohort, high CD8+ T cell infiltration was associated with better overall survival (p = 0.040), particularly in the EBV-positive (p = 0.036) and CIN (p = 0.065) subtypes, but not in MSI (p = 0.440) or GS (p = 0.860). Notably, low CD8+ T infiltration predicted superior response to adjuvant chemotherapy in MSI patients (HR = 0.210, p = 0.022). Immune profiling revealed associations of CD8+ T cells with antigen presentation in EBV-positive, tertiary lymphoid structure signatures in CIN, and podoplanin+ cells in GS tumors, instead of neoantigen burden in MSI or pan-fibroblast TGFβ response signature in GS. CD8+ T cell infiltration demonstrates subtype-specific prognostic and therapeutic significance in GC-beneficial in EBV-positive and CIN tumors, and predictive of chemotherapy response in MSI with low infiltration, which accompanied by divergent immune features, reflecting heterogeneous immunological landscape of GC.

Keywords:  CD8+ T cell; TCGA subtype; adjuvant chemotherapy; gastric cancer; immune microenvironment

DOI:  https://doi.org/10.1111/cas.70366
Int J Cancer. 2026 Mar 16.

Sequential personalized neoantigen vaccination following first-line treatments demonstrates safety and efficacy in advanced hepatocellular carcinoma.

Zhixiong Cai, Liman Qiu, Ling Li, Zhenli Li, Kailiang Zhang, Yan Lin, Yang Zhou, Xiuqing Dong, Geng Chen, Rong Xie, Jianhui Lin, Yongyi Zeng, Haijun Yu, Zhuting Fang, Wuhua Guo, Xinhui Huang, Xiaolong Liu.

  Hepatocellular carcinoma (HCC) has limited therapeutic options in the advanced stages; although first-line combinations of transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) and/or programmed cell death protein 1 (PD-1) inhibitors show promise, their efficacy is constrained by inadequate tumor-specific T-cell infiltration. To address this limitation, we conducted an investigator-initiated, single-center clinical trial (ChiCTR2300067818) evaluating the safety, feasibility, and preliminary efficacy of sequential personalized neoantigen vaccination following TACE plus TKI/PD-1-based therapy in patients with advanced HCC. Whole-exome and transcriptome sequencing identified patient-specific neoantigens, which were synthesized as long peptides and formulated with dual adjuvants for subcutaneous administration. Among 10 initially enrolled patients, 4 received personalized vaccination after comprehensive screening, with 2 patients (N03 and N04) completing the full 8-injection vaccination regimen. Sequential neoantigen vaccination demonstrated excellent safety profiles, with only mild injection-site reactions observed. Both patients achieved partial response following vaccination. Interferon-gamma Enzyme-Linked ImmunoSpot assays confirmed robust neoantigen-specific responses against multiple peptide pools in both patients. Dynamic monitoring revealed that serum alpha-fetoprotein and Des-gamma-carboxy prothrombin levels correlated with clinical responses, declining significantly during vaccination. These findings demonstrate that sequential personalized neoantigen vaccination following first-line TACE-based therapy is safe, feasible, and capable of inducing potent tumor-specific immune responses, supporting further investigation in larger clinical trials.

Keywords:  hepatocellular carcinoma; immunotherapy; personalized neoantigen vaccination; tumor‐specific immune responses

DOI:  https://doi.org/10.1002/ijc.70445
bioRxiv. 2026 Mar 08. pii: 2026.03.05.709907. [Epub ahead of print]

IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer.

Lupita S Lopez, Ziyou Cui, Yukiko Yamaguchi, John P Murad, Zhiyuan Yang, Ke Zou, Jason Yang, Wen-Chung Chang, Stephen J Forman, Vivien W Chan, Saul J Priceman.

Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single chain variable fragment (scFv) derived from the humanized murine mAb clone, J591, as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFNy production and anti-tumor cell activity in vitro . Using two clinically-relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.

DOI: https://doi.org/10.64898/2026.03.05.709907
Cancer Immunol Res. 2026 Mar 19.

FOXM1-specific TCR-engineered T cells target non-small cell lung cancer.

Emily Bontekoe, Minying Zhang, Peixin Jiang, Amanda Montoya, Yulia Shulga, Jared K Slone, Emily Paul, Christopher Polera, Sarah Forward, Barbara Nassif Rausseo, Emane Rose Assita, Changsheng Xing, David P Molkentine, Benjamin B Morris, Isabella Polic, Janos Roszik, Ricardo Salgado, Aria Vaishnavi, Drew Deniger, Hai T Tran, Don L Gibbons, Ara Vaporciyan, Maura L Gillison, Ignacio I Wistuba, Lydia E Kavraki, Jianjun Zhang, Gregory Lizee, Cassian Yee, Patrick Hwu, Sheldon Kwok, Alex M Jaeger, John V Heymach, Alexandre Reuben.

FOXM1 is highly expressed in various cancer types and considered a key driver of cancer progression. Accordingly, we evaluated the immunogenicity of FOXM1 and investigated the feasibility of targeting this transcription factor using T cell receptor (TCR) engineering. We identified epitopes derived from FOXM1 which were immunogenic on HLA-A*02:01, HLA-A*24:02, and HLA-A*23:01, endogenously-processed and presented, and resulted in T cell activation and cytotoxic T cell responses. Following the generation of TCR-T cells, sensitivity and specificity were confirmed by peptide dose-response and X-scan, respectively. Most importantly, adoptive transfer of TCR engineered T cells led to a significant reduction in tumor growth, as well as significantly prolonged survival in a tumor-bearing immunocompromised murine model. Our studies confirm the immunogenicity of FOXM1 and feasibility of targeting this antigen using TCR-engineering.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0605
J Immunol. 2026 Mar 17. pii: vkag004. [Epub ahead of print]215(3):

B cell depletion promotes melanoma tumor growth in a CD4+ T cell-dependent manner.

Selin Oncul, Hani Lee, Shailbala Singh, Cassian Yee, Vahid Afshar-Kharghan.

  B cells constitute ∼15% to 20% of tumor-infiltrating lymphocytes in melanoma. Their presence in the tumor microenvironment correlates with improved survival and enhanced response to immune checkpoint blockade therapy. Yet, the functional contribution of B cells to melanoma immunity remains unclear. In this study, we showed that both genetic and antibody-mediated B cell depletion significantly promoted melanoma progression in mice. Immune profiling revealed that, although B cell percentages were reduced, IL-10-producing B regulatory cells (Bregs) persisted after depletion. However, the persistence of Bregs alone cannot explain the impact of B cell depletion on enhancing melanoma growth, as codepletion of B cells and CD4+ T cells, despite similar Breg levels, did not promote melanoma progression. B cell depletion also resulted in the accumulation of PD-1+ B cells, CD4+ T cells, and monocytic myeloid-derived suppressor cells into the tumor microenvironment, alongside a reduction in IFN-γ+CD8+ T cells, CXCL13+CD8+ T cells, and M1-like macrophages. Notably, plasma cell deficiency did not affect tumor growth, indicating that B cell-mediated antitumor activity is independent of antibody production. The tumor-promoting effect of B cell loss was at least partially CD4+ T cell dependent, as codepletion of B cells and CD4+ T cells reversed this phenotype and B cell depletion did not enhance tumor growth in Nu/Nu mice lacking mature T cells. Taken together, our findings reveal an antitumor role of B cells in melanoma and demonstrate that their loss promotes tumor progression through reprogramming of the tumor immune microenvironment.

Keywords:  B cells; Bregs; CD4+ T cells; melanoma; tumor microenvironment

DOI:  https://doi.org/10.1093/jimmun/vkag004
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2522872123

Regulation of the immune CD155-CD226-TIGIT axis by cyclin D-CDK4/6.

Anne Fassl, Miriam Palacios Espinoza, Deborah Butter, Aleksandra Kolodziejczyk, Marco Seehawer, Charlotte Hill, Xiaohan Ning, Timothy B Branigan, Johany Peñailillo, Charupong Saengboonmee, Heta Jadhav, Louis-Marie Charbonnier, Adrienne G Waks, Corinne Strawser, Donald P McDonnell, Geoffrey I Shapiro, Sara M Tolaney, Kornelia Polyak, Sarah Sammons, Kai W Wucherpfennig, Piotr Sicinski.

  Cyclin D-CDK4/6 is a component of mammalian cell-cycle machinery that drives cell proliferation. Small-molecule inhibitors of CDK4/6 have been approved for treatment of breast cancer patients. In addition to halting cell-cycle progression, inhibition of CDK4/6 can affect other tumor cell-intrinsic and -extrinsic functions. Here, we examined the impact of CDK4/6 inhibition on the CD155-CD226-TIGIT pathway that operates at the interface of tumor cells and the immune environment. We demonstrate that inhibition of CDK4/6 upregulates the expression of surface CD155 protein in cancer cells and downregulates an immuno-inhibitory receptor TIGIT in tumor-infiltrating lymphocytes. We observed these effects in human breast cancer cell lines, in mouse mammary carcinoma allograft models, in freshly resected human breast tumors and in paired pre-/on-treatment biopsies of breast cancers from patients undergoing monotherapy with a CDK4/6 inhibitor. We propose that inhibition of CDK4/6, through its tumor cell-intrinsic and -extrinsic effects, may shift the balance from the immunoinhibitory CD155-TIGIT to the immunostimulatory CD155-CD226 interaction, and through this mechanism may augment the antitumor immunity. Our results suggest that coadministration of CDK4/6 inhibitors and anti-TIGIT antibodies may further promote CD155-CD226-signaling and may have a strong synergistic antitumor effect.

Keywords:  CD155; CDK4/6; TIGIT; breast cancer; cell cycle

DOI:  https://doi.org/10.1073/pnas.2522872123
J Clin Invest. 2026 Mar 16. pii: e195668. [Epub ahead of print]136(6):

T cell-intrinsic VISTA expression promotes resistance to CTLA-4 blockade by restricting CD8+ T cell responses.

Cassandra Gilmour, Elizabeth DeLaney, Prerana B Parthasarathy, Dia Roy, Hieu M Ta, Amin Zakeri, Paolo Elguera Grandez, Sachin Patnaik, Keman Zhang, Ivan Juric, Rahul Rangan, Zahraa Al-Hilli, Anthony Tufaro, Booki Min, Samuel E Weinberg, Timothy A Chan, Natalie L Silver, Stefanie Avril, Tyler Alban, Li Lily Wang.

  V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint protein that impairs antitumor T cell responses. While broadly expressed on myeloid cells and T cells, the specific contribution of T cell-intrinsic VISTA to antitumor immunity remains undefined. This study investigated the phenotypic and functional consequences of T cell-specific VISTA deletion in tumor-specific CD8+ T cells. Single-cell transcriptomic analysis, TCR repertoire profiling, and flow cytometry revealed that loss of T cell-intrinsic VISTA enhanced early priming and short-term expansion of CD8+ T cells, yet this initial advantage failed to confer durable tumor control. Persistent dysfunction in VISTA-deficient T cells was in part driven by trans-VISTA on myeloid cells, while CTLA-4 upregulation further constrained T cell responses. T cell-intrinsic VISTA deficiency cooperated with CTLA-4 blockade to improve T cell survival and broaden TCR repertoire diversity, resulting in more robust tumor regression than CTLA-4 inhibition alone. A transcriptional signature enriched in VISTA-deficient cytotoxic T cells correlated with favorable outcomes in cancer patients treated with existing immune checkpoint inhibitors. These findings collectively define T cell-intrinsic mechanisms by which VISTA enforces T cell dysfunction and underscore its potential as both a therapeutic target and a biomarker of resistance to current immunotherapies.

Keywords:  Adaptive immunity; Cancer immunotherapy; Cellular immune response; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI195668
Nat Biotechnol. 2026 Mar 18.

Sustained nitric oxide production by engineered E. coli remodels the tumor microenvironment and potentiates immunotherapy.

Shuyu Xu, Tianjiao Zhang, Yang Song, Mengxin Wang, Ruiqi Wu, Mofan Li, Haonan Wang, Xinxin Xie, Qingfeng Chen, Xiaotu Ma, Xiaolong Liang.

Tumor immunotherapy is often compromised by an immunosuppressive tumor microenvironment (TME) characterized by abnormal vasculature and exhausted T cells. Here, given the role of nitric oxide (NO) in favorably remodeling the TME, we engineered Escherichia coli Nissle 1917 (ECN) with a synthetic arginine-NO circuit (ECN-NO) that modifies the arginine synthesis pathway to constitutively synthesize arginine and enable sustained NO production. Specifically, deletion of the arginine repressor ArgR relieved feedback inhibition of arginine biosynthesis, whereas co-expression of argininosuccinate synthase and lyase (ArgG/ArgH), together with Bacillus subtilis nitric oxide synthase (BsNOS), enabled sustained NO production through enhanced arginine regeneration. Intratumoral colonization of ECN-NO significantly enhanced the antitumor efficacy of anti-programmed cell death ligand 1 (αPD-L1) immunotherapy, resulting in durable tumor regression across multiple solid tumor mouse models. Mechanistically, ECN-NO induced vascular normalization and dendritic cell recruitment, alleviated tumor immunosuppression and synergized with αPD-L1 to expand functional CD8+ T cells, reverse T cell exhaustion and promote memory T cell formation, establishing antitumor immunity for at least 120 days.

DOI: https://doi.org/10.1038/s41587-026-03054-y
Chin Med J (Engl). 2026 Mar 17.

Endogenous glucocorticoids and glucocorticoid receptor signaling: Dual regulators of PD-1/PD-L1 immunotherapy efficacy in the tumor microenvironment.

Fanyu Guo, Benling Xu, Guangyu Chen, Jiaqi Liu, Quanli Gao.

   ABSTRACT: Immunotherapy targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has significantly improved outcomes for various cancers, yet the emergence of resistance remains a major challenge. This review focuses on the dual role of endogenous glucocorticoids (GCs) and their receptor (GR) within the tumor microenvironment (TME), systematically elucidating the mechanisms by which they regulate responses to PD-1/PD-L1 therapy via the hypothalamic-pituitary-adrenal (HPA) axis, local synthesis and metabolism, and heterogeneity of GR signaling. We elaborate on the regulatory effects of the GC/GR signaling pathway on immune cells (such as cluster of differentiation 8 positive [CD8 + ] T cells, regulatory T cells [Tregs], dendritic cells, natural killer [NK] cells, and macrophages), and highlight the impact of GCs on PD-L1 expression, cytokine secretion, and the immunosuppressive microenvironment. This review also explores the controversial role of exogenous GCs in managing immune-related adverse events (irAEs) and their potential impact on therapeutic efficacy. The development of tissue-selective GR modulators holds promise for balancing immunosuppression while enhancing anti-tumor activity. A deeper understanding of the role of endogenous GCs in cancer immunotherapy is crucial for optimizing therapeutic strategies, overcoming resistance, and finally achieving precision in cancer immunotherapy.

Keywords:  Cancer immunotherapy; Glucocorticoid receptor; Glucocorticoids; PD-1/PD-L1 blockade; Tumor microenvironment

DOI:  https://doi.org/10.1097/CM9.0000000000003956