bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–05–18
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Correspondence on "The prognostic value of tumor-infiltrating lymphocytes in vulvovaginal melanoma" by Vanbockstael et al.
  2. Harnessing Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Opportunities and Barriers to Clinical Integration.
  3. Clinical Significance of Tumor-Infiltrating Lymphocytes in Malignant Peritoneal Mesothelioma: A Single-Center Study of 143 Cases.
  4. Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer.
  5. Different MRI-based radiomics machine learning models to predict CD3+ tumor-infiltrating lymphocytes in rectal cancer.
  6. A Systematic Review of Immune Cell Roles in Breast Cancer Immunotherapy.
  7. Multi-assistant methods improve stromal tumor-infiltrating lymphocytes (sTILs) assessment in breast cancer: results of multi-institutional ring studies.
  8. Cell-based immunotherapies for solid tumors: advances, challenges, and future directions.
  9. Targeted activation of junctional adhesion molecule-like protein+ CD8+ T cells enhances immunotherapy in hepatocellular carcinoma.
  10. Oncolytic Adenovirus Armoring with CXCL9 and IL15 Shows Potent Antitumor Activity and Boosts CAR-T Therapy for Prostate Cancer.
  11. Generation of T cell responses against broad KRAS hotspot neoantigens for cell therapy or TCR discovery.
  12. Advances in T Cell-Based Cancer Immunotherapy: From Fundamental Mechanisms to Clinical Prospects.
  13. CD8+ T cells in breast cancer tumors and draining lymph nodes: PD-1 levels, effector functions and prognostic relevance.
  14. TIGIT blockade increases efficacy of PD-1 blockade combined with radiation therapy in triple-negative breast cancer model.
  15. mRNA lipid nanoparticles in CAR-T therapy: a novel strategy to improve efficacy.
  16. In vivo RNAi screen and validation reveals Ngp, Hba-a1, and S100a8 as novel inhibitory targets on T lymphocytes in liver cancer.
  1. Int J Gynecol Cancer. 2025 Mar 21. pii: S1048-891X(25)00909-0. [Epub ahead of print]35(6): 101792
    Correspondence on "The prognostic value of tumor-infiltrating lymphocytes in vulvovaginal melanoma" by Vanbockstael et al.
    Wiebren Age Andries Tjalma.
      
    DOI:  https://doi.org/10.1016/j.ijgc.2025.101792
  2. Int J Mol Sci. 2025 May 01. pii: 4292. [Epub ahead of print]26(9):
    Harnessing Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Opportunities and Barriers to Clinical Integration.
    Cara Coleman, Tharakeswari Selvakumar, Aswani Thurlapati, Kevin Graf, Sushma Pavuluri, Shikhar Mehrotra, Ozgur Sahin, Abirami Sivapiragasam.
      Triple-negative breast cancer (TNBC) continues to present a therapeutic challenge due to the fact that by definition, these cancer cells lack the expression of targetable receptors. Current treatment options include cytotoxic chemotherapy, antibody-drug conjugates (ADC), and the PD-1 checkpoint inhibitor, pembrolizumab. Due to high rates of recurrence, current guidelines for early-stage TNBC recommend either multi-agent chemotherapy or chemo-immunotherapy in all patients other than those with node-negative tumors < 0.5 cm. This approach can lead to significant long-term effects for TNBC survivors, driving a growing interest in de-escalating therapy where appropriate. Tumor infiltrating lymphocytes (TILs) represent a promising prognostic and predictive biomarker for TNBC. These diverse immune cells are present in the tumor microenvironment and within the tumor itself, and multiple retrospective studies have demonstrated that a higher number of TILs in early-stage TNBC portends a favorable prognosis. Research has also explored the potential of TIL scores to predict the response to immunotherapy. However, several barriers to the widespread use of TILs in clinical practice remain, including logistical and technical challenges with the scoring of TILs and lack of prospective trials to validate the trends seen in retrospective studies. This review will present the current understanding of the role of TILs in TNBC and discuss the future directions of TIL research.
    Keywords:  triple-negative breast cancer; tumor infiltrating lymphocytes; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26094292
  3. Ann Surg Oncol. 2025 May 15.
    Clinical Significance of Tumor-Infiltrating Lymphocytes in Malignant Peritoneal Mesothelioma: A Single-Center Study of 143 Cases.
    He-Liang Wu, Rui Yang, Xin-Li Liang, Ru Ma, Yan-Dong Su, Zhi-Ran Yang, Yu-Run Cui, Xue-Mei Du, Yi-Tong Liu, Yan Li.
       BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignant tumor with high mortality rate and extremely poor prognosis. The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response. This study aimed to analyze the correlation between the level of TILs and the main clinicopathological characteristics and prognosis of MPM.
    PATIENTS AND METHODS: A total of 143 postoperative specimens from patients with MPM following cytoreductive surgery were collected. Postoperative specimens were stained with hematoxylin and eosin (H&E). The level of TILs was quantitatively analyzed by QuPath 0.3.2 software. Univariate and multivariate analyses were conducted to investigate the correlation between TILs level and other conventional clinicopathological characteristics.
    RESULTS: Among the 143 patients with MPM, 73 were male (51.0%) and 70 were female (49.0%), with a median age of 55 (range 24-73) years. There were 72 (50.3%) cases with low TILs, and 71 (49.7%) cases with high TILs. Univariate analysis showed that TIL level (low versus high) was negatively correlated with the following seven clinicopathological factors: surgery history, Ki-67 index, preoperative CA125 level, peritoneal cancer index (PCI) index, bleeding volume, red blood cell (RBC) transfusion volume, and ascites volume (all P < 0.05). Multivariate analysis indicated that TIL level was independently negatively correlated with preoperative carbohydrate antigen (CA)125 level (odds ratio 0.394, 95% CI 0.179-0.866, P = 0.020). Cox regression analysis suggested that high TILs was independently associated with better prognosis of MPM. Moreover, a cohort of patients who received preoperative chemotherapy combined with targeted therapy were evaluated for response. Kaplan-Meier curve showed that high infiltration of TILs predicted better overall survival in patients undergoing treatment.
    CONCLUSIONS: TILs could be a useful indicator for predicting prognosis and guiding personalized treatment strategies in patients with MPM.
    Keywords:  Clinical significance; Malignant peritoneal mesothelioma; Microenvironment; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1245/s10434-025-17437-z
  4. Cancers (Basel). 2025 Apr 25. pii: 1435. [Epub ahead of print]17(9):
    Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer.
    Philip B Emmerich, Tonela Qyli, Katherine A Johnson, Somak Chaudhuri, Kristen M Clark, Nathaniel B Verhagen, Mitchell G Depke, Linda Clipson, Cheri A Pasch, Athanasios Papadas, Mark E Burkard, Kari B Wisinski, Stephanie M McGregor, Fotis Asimakopoulos, Dustin A Deming.
      Background/Objectives: Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict the exclusion of CD8+ tumor-infiltrating lymphocytes (TILs) in some settings and, thus, is evaluated in breast cancer here. Methods: A total of 230 breast cancers were analyzed for VCAN accumulation, VCAN proteolysis, and CD8+ TILs. CD8+ TILs were categorized based on their localization in the tumor epithelial or stromal compartments. Results: VCAN accumulation was detected in 90% of breast cancers, more commonly in ER+ tumors (93% vs. 77%; p < 0.001). MCF7 cells treated with estrogen upregulate VCAN without an enhanced expression of ADAMTS-proteases. VCAN-undetectable tumors demonstrate greater CD8+ TILs compared to VCAN-detectable tumors (p = 0.012). CD8+ T cells within TNBC tumors with high VCAN proteolysis infiltrated the epithelial compartment more often than in tumors with low VCAN proteolysis (91% vs. 42% respectively; p = 0.008). In the TCGA cohort, a strong inverse correlation between CD8A and VCAN expression was observed across subtypes. Conclusions: VCAN accumulation correlates with the exclusion of CD8+ TILs across subtypes of breast cancer, warranting further validation of VCAN accumulation and proteolysis as predictive biomarkers for breast cancer immunotherapy.
    Keywords:  CD8+ TILs; breast cancer; estrogen receptor; versican; versikine
    DOI:  https://doi.org/10.3390/cancers17091435
  5. Front Oncol. 2025 ;15 1509207
    Different MRI-based radiomics machine learning models to predict CD3+ tumor-infiltrating lymphocytes in rectal cancer.
    Weili Ma, Chuanling Hou, Minxia Yang, Yuguo Wei, Jiwei Mao, Le Guan, Zhenhua Zhao.
       Objectives: This study aimed to develop and evaluate multiple machine learning models utilizing contrast-enhanced T1-weighted imaging (T1-CE) to differentiate between low-/high-infiltration of total T lymphocytes (CD3) in patients with rectal cancer.
    Methods: We retrospectively selected 157 patients (103 men, 54 women) with pathologically confirmed rectal cancer diagnosed between March 2015 and October 2019. The cohort was randomly divided into a training dataset (n=109) and a test dataset (n=48) for subsequent analysis. Seven radiomic features were selected to generate three models: logistic regression (LR), random forest (RF), and support vector machine (SVM). The diagnostic performance of the three models was compared using the DeLong test. Additionally, Kaplan-Meier analysis was employed to assess disease-free survival (DFS) in patients with high and low CD3+ tumor-infiltrating lymphocyte (TIL) density.
    Results: The three radiomics models performed well in predicting the infiltration of CD3+ TILS, with area under the curve (AUC) values of 0.871, 0.982, and 0.913, respectively, in the training set for the LR, RF, and SVM models. In the validation set, the corresponding AUC values were 0.869, 0.794, and 0.837, respectively. Among the radiomics models, the LR model exhibited superior diagnostic performance and robustness. The merged model, which integrated radiomics features from the SVM model and clinical features from the clinical model, outperformed the individual radiomics models, with AUCs of 0.8932 and 0.8829 in the training and test cohorts, respectively. Additionally, a lower expression level of CD3+ TILs in the cohort was independently correlated with DFS (P = 0.0041).
    Conclusion: The combined model demonstrated a better discriminatory ability in assessing the abundance of CD3+ TILs in rectal cancer. Furthermore, the expression of CD3+ TILs was significantly correlated with DFS, highlighting its potential prognostic value.
    Advances in knowledge: This study is the first attempt to compare the predictive TILs performance of three machine learning models, LR, RF, and SVM, based on the combination of radiomics and immunohistochemistry. The MRI-based combined model, composed of radiomics features from the SVM model and clinical features from the clinical model, exhibited better discriminatory capability for the expression of CD3+ TILs in rectal cancer.
    Keywords:  CD3; machine learning; radiomics; rectal cancer; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fonc.2025.1509207
  6. Cancer Rep (Hoboken). 2025 May;8(5): e70217
    A Systematic Review of Immune Cell Roles in Breast Cancer Immunotherapy.
    Rui Li, Wei Lv, Dong Liang Wang, Na Chen.
       BACKGROUND: Breast cancer (BC) is the most prevalent malignancy among women and is associated with high mortality and significant clinical challenges. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have significantly improved patient survival, their efficacy remains limited by severe side effects and treatment resistance. In recent years, advances in immunotherapy have underscored the pivotal role of immune cells in treating BC.
    RECENT FINDINGS: This systematic review summarizes the current knowledge on the roles of immune cells within the BC tumor microenvironment (TME), including their phenotypes, functions, and implications for immunotherapy. Following PRISMA guidelines, 71 studies published between 2010 and 2024 were analyzed. The results indicate that immune cell populations-such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs)-are integral to tumor progression and therapeutic response. However, their functional heterogeneity and plasticity remain key obstacles to the development of effective and personalized immunotherapeutic strategies.
    CONCLUSION: Further research is needed to clarify the mechanisms governing immune cell behavior within the BC TME and to advance precision immunotherapy. Such insights will lay the foundation for individualized treatment approaches, ultimately improving patient outcomes and quality of life (QoL).
    Keywords:  breast cancer; immune cells; immunotherapy; tumor microenvironment; vaccines
    DOI:  https://doi.org/10.1002/cnr2.70217
  7. ESMO Open. 2025 May 14. pii: S2059-7029(25)00964-0. [Epub ahead of print]10(5): 105095
    Multi-assistant methods improve stromal tumor-infiltrating lymphocytes (sTILs) assessment in breast cancer: results of multi-institutional ring studies.
    M Zhao, P Dong, Z Li, J Li, S Wu, H Xing, P Zhang, J Zhang, H Shen, H Yang, W Yang, X Han, Y Liu.
       BACKGROUND: Stromal tumor-infiltrating lymphocytes (sTILs) have significant prognostic value for breast cancer patients, but its accurate assessment can be very challenging. We comprehensively studied the pitfalls faced by pathologists with different levels of professional experience, and explored clinical applicability of reference cards (RCs)- and artificial intelligence (AI)-assisted methods in assessing sTILs.
    MATERIALS AND METHODS: Three rounds of ring studies (RSs) involving 12 pathologists from four hospitals were conducted. AI algorithms based on the field of view (FOV) and whole section were proposed to create RCs and to compute whole-slide image interpretations, respectively. Stromal regions identified and the associated sTIL scores by the AI method were provided to the pathologists as references. Fifty cases of surgical resections were used for interobserver concordance analysis in RS1. A total of 200 FOVs with challenge factors were assessed in RS2 for accuracy of the RC-assisted and AI-assisted methods, while 167 cases were used to validate their clinical performance in RS3.
    RESULTS: With the assistance of RCs, the intraclass correlation coefficient (ICC) in RS1 increased significantly to 0.834 [95% confidence interval (CI) 0.772-0.889]. The largest enhancement in ICC, from moderate (ICC: 0.592; 95% CI 0.499-0.677) to good (ICC: 0.808; 95% CI 0.746-0.857) was observed for heterogeneity. Accuracy evaluation showed significant grade improvement for heterogeneity and stromal factor FOVs among senior, intermediate, and junior groups. The ICC of heterogeneity and stromal factor analysis by the AI-assisted method achieved a level comparable to that of the senior group with RC assistance. The area under the receiver operating characteristic (ROC) curve, denoted as AUC, for AI-assisted sTIL scores in predicting pathological complete response after neoadjuvant therapy was 0.937, which was superior to visual assessment with an AUC of 0.775.
    CONCLUSION: RC- and AI-assisted technology can reduce the uncertainty of interpretation caused by heterogeneous distribution.
    Keywords:  AI; breast cancer; concordance; reference card; stromal TILs
    DOI:  https://doi.org/10.1016/j.esmoop.2025.105095
  8. Front Oncol. 2025 ;15 1551583
    Cell-based immunotherapies for solid tumors: advances, challenges, and future directions.
    Ting Zhao, Jinping You, Congyue Wang, Bo Li, Yuhan Liu, Mingjia Shao, Wuyang Zhao, Chuang Zhou.
      Cell-based immunotherapies, including CAR-T, CAR-NK, and TCR-T therapies, represent a transformative approach to cancer treatment by offering precise targeting of tumor cells. Despite their success in hematologic malignancies, these therapies encounter significant challenges in treating solid tumors, such as antigen heterogeneity, immunosuppressive tumor microenvironments, limited cellular infiltration, off-target toxicity, and difficulties in manufacturing scalability. CAR-T cells have demonstrated exceptional efficacy in blood cancers but face obstacles in solid tumors, whereas CAR-NK cells offer reduced graft-versus-host disease but encounter similar barriers. TCR-T cells expand the range of treatable cancers by targeting intracellular antigens but require meticulous antigen selection to prevent off-target effects. Alternative therapies like TIL, NK, and CIK cells show promise but require further optimization to enhance persistence and overcome immunosuppressive barriers. Manufacturing complexity, high costs, and ensuring safety and efficacy remain critical challenges. Future advancements in gene editing, multi-antigen targeting, synthetic biology, off-the-shelf products, and personalized medicine hold the potential to address these issues and expand the use of cell-based therapies. Continued research and innovation are essential to improving safety, efficacy, and scalability, ultimately leading to better patient outcomes.
    Keywords:  CAR-NK; CAR-T; TCR-T; cell-based immunotherapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1551583
  9. Chin J Cancer Res. 2025 Apr 30. 37(2): 212-226
    Targeted activation of junctional adhesion molecule-like protein+ CD8+ T cells enhances immunotherapy in hepatocellular carcinoma.
    Huan Chen, Zhaofeng Xiao, Zhengyang Lu, Nan Xu, Qiang Wei, Xiao Xu.
       Objective: Cytotoxic T lymphocytes (CTLs) play a crucial role in the therapeutic approach to hepatocellular carcinoma (HCC). Recent research has indicated that junctional adhesion molecule-like protein (JAML) enhances the antitumor activity of CD8+ T cells. Our study investigates the role of JAML+ CD8+ T cells in HCC.
    Methods: We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy. Flow cytometry was used to assess CD4+ T cells differentiation and JAML expression in CD8+ T cells infiltrating HCC. Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+ (LDHA+) CD4+ T cells and JAML+ CD8+ T cells. Subsequently, we evaluated the therapeutic effects of an agonistic anti-JAML antibody, both alone and combined with immunotherapy. Finally, RNA sequencing was conducted to identify potential regulatory mechanisms.
    Results: Immunotherapy significantly increased the percentage of CD8+ T cells infiltrating HCC and induced histone modifications, such as H3K18 lactylation (H3K18la) in CD4+ T cells. Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+ T cells into Th1 cells. LDHA, an enzyme that converts pyruvate to lactate, plays a key role in this process. Correlation analysis revealed a strong positive relationship between LDHA+ CD4+ T cells and JAML+ CD8+ T cells in patients who responded to immunotherapy. Moreover, high JAML expression in CD8+ T cells was associated with a more favorable prognosis. In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice, independent of the effects of anti-programmed cell death protein ligand-1 antibody (αPD-L1)-mediated immunotherapy. Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.
    Conclusions: Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.
    Keywords:  H3K18la; Hepatocellular carcinoma; immunotherapy; junctional adhesion molecule-like protein; oxidative phosphorylation
    DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.02.08
  10. Hum Gene Ther. 2025 May 09.
    Oncolytic Adenovirus Armoring with CXCL9 and IL15 Shows Potent Antitumor Activity and Boosts CAR-T Therapy for Prostate Cancer.
    Lin Fang, Xueyan Wang, Yi Zhang, Chen Zhang, Xiaoxiao Liu, Wanjing Li, Yuxin Zhang, Nan Sun, Junnian Zheng, Gang Wang.
      Chimeric antigen receptor T cell (CAR-T) therapy has achieved great success and progress for treatment of hematological malignancy, but it still cannot overcome the obstacles in solid tumors. The hostile tumor microenvironment (TME), such as dense extracellular matrix, hypoxia, low pH, and tumor-derived metabolites, largely impedes CAR-T function. Oncolytic virus, as a form of immunotherapy, provides a way to antagonize the TME and improve the efficacy of CAR-T cells in solid tumors. In this study, the chemokine CXCL9 and interleukin 15 (IL15) genes were genetically integrated into adenoviral vector to construct oncolytic adenovirus (OAV) Ad-CXCL9-IL15, which could infect tumor cells to express and secrete CXCL9 and IL15. Ad-CXCL9-IL15 showed potent antitumor activity in xenografted prostate cancer model and augmented the tumor infiltration of CD45+CD3+ T and CD8+ T cells in immunocompetent mice. Moreover, Ad-CXCL9-IL15 treatment decreased Treg cells in tumor mass and increased CD44+CD62L+ T cells in spleen. Indicating that Ad-CXCL9-IL15 modified the TME and augmented antitumor immune responses in vivo. Furthermore, administration of Ad-CXCL9-IL15 dramatically promoted infiltration and survival of B7H3-targeting CAR-T cells, improved the therapeutic efficacy, and prolonged the survival time of prostate cancer-bearing mice. Therefore, cytokine-armored OAV Ad-CXCL9-IL15 could be used as a bioenhancer to modify TME and boost immunotherapy for solid tumors.
    Keywords:  CXCL9; IL15; chimeric antigen receptor T cell; oncolytic adenovirus; prostate cancer
    DOI:  https://doi.org/10.1089/hum.2024.254
  11. Cell Rep Methods. 2025 May 07. pii: S2667-2375(25)00085-2. [Epub ahead of print] 101049
    Generation of T cell responses against broad KRAS hotspot neoantigens for cell therapy or TCR discovery.
    Brandon P Conn, Jared L Dietze, Christian J Yee, Margaret M Hallisey, Irais Ortiz-Caraveo, Marit M van Buuren, Richard B Gaynor, Kendra C Foley, Jaewon Choi, Vikram R Juneja.
      Adoptive cell therapy (ACT) with T cells targeting Kirsten rat sarcoma (KRAS) neoantigens can drive anti-tumor immunity but has so far been focused on a small fraction of known KRAS neoantigens. Here, we develop a single process starting from peripheral blood that can prime and expand T cell responses ex vivo to any KRAS neoantigen based on each individual's human leukocyte antigen (HLA) profile. We conducted the process in 20 healthy donors and generated T cell responses to 46 of 47 evaluated neoantigens. We identified and cloned more than 150 KRAS T cell receptors (TCRs), with the strongest TCRs having similar potency to clinically active benchmark TCRs. T cells generated through this process were able to slow tumor growth in vitro and in vivo. The approach could be used as the basis for the development of an ex vivo primed therapeutic or to discover a library of TCRs against a broad range of KRAS neoantigens.
    Keywords:  CP: biotechnology; CP: immunology; KRAS; T cell; TCR; adoptive cell transfer; cancer; immunotherapy; neoantigen
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101049
  12. Mol Pharm. 2025 May 13.
    Advances in T Cell-Based Cancer Immunotherapy: From Fundamental Mechanisms to Clinical Prospects.
    Kaili Zhang, Yi Zhang, Pan Xiang, Yi Wang, Yifan Li, Shuze Jiang, Yuxuan Zhang, Min Chen, Weijun Su, Xiaoling Li, Shuai Li.
      T cells and their T cell receptors (TCRs) play crucial roles in the adaptive immune system's response against pathogens and tumors. However, immunosenescence, characterized by declining T cell function and quantity with age, significantly impairs antitumor immunity. Recent years have witnessed remarkable progress in T cell-based cancer treatments, driven by a deeper understanding of T cell biology and innovative screening technologies. This review comprehensively examines T cell maturation mechanisms, T cell-mediated antitumor responses, and the implications of thymic involution on T cell diversity and cancer prognosis. We discuss recent advances in adoptive T cell therapies, including tumor-infiltrating lymphocyte (TIL) therapy, engineered T cell receptor (TCR-T) therapy, and chimeric antigen receptor T cell (CAR-T) therapy. Notably, we highlight emerging DNA-encoded library technologies in mammalian cells for high-throughput screening of TCR-antigen interactions, which are revolutionizing the discovery of novel tumor antigens and optimization of TCR affinity. The review also explores strategies to overcome challenges in the solid tumor microenvironment and emerging approaches to enhance the efficacy of T cell therapy. As our understanding of T cell biology deepens and screening technologies advances, T cell-based immunotherapies show increasing promise for delivering durable clinical benefits to a broader patient population.
    Keywords:  Adoptive T cell therapy; Cancer immunoediting; DNA-encoded libraries; T cell-based immunotherapy; TCR engineering
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c01502
  13. Oncoimmunology. 2025 Dec;14(1): 2502354
    CD8+ T cells in breast cancer tumors and draining lymph nodes: PD-1 levels, effector functions and prognostic relevance.
    Carolina Abrate, Fernando P Canale, Sabrina N Bossio, Jimena Tosello Boari, María C Ramello, Nicolas Nuñez, Wilfrid Richer, Christine Sedlik, Jordan Denizeau, Anne Vincent-Salomon, Edith Borcoman, Andres Del Castillo, Adriana Gruppi, Eva V Acosta Rodríguez, Eliane Piaggio, Carolina L Montes.
      CD8+ T cells shape the antitumor immune response. Here, we evaluated CD8+ T cells expressing different levels of PD-1, their functional status, and distribution in different tissues of luminal breast cancer (BC) patients. We characterized the exhaustion stages of CD8+ T cells in tumors, juxtatumoral tissues (JTs), and tumor-draining lymph nodes (TDLNs). Terminal exhausted CD8+ T cells (PD-1High CD8+) were predominant in tumors and nearly absent in other tissues. However, in all tissues evaluated, most CD8+ T cells exhibited a pre-exhausted phenotype (PD-1Int CD8+) or did not express PD-1. PD-1High and PD-1Int CD8+ T cells from tumors and JTs presented central and effector memory phenotypes, while in TDLNs were primarily central memory. TCR-β sequencing revealed higher clonality among CD8+ T cells from tumor than TDLNs, with tumor-enriched clones also detected in TDLNs. Analysis of scRNA-seq datasets from tumors and JTs of colorectal and non-small cell lung cancer patients, identified a CD8+ terminal exhaustion and a CD8+ pre-exhausted signatures. High expression of exhaustion-associated genes in BC tumors correlated with improved overall survival. Overall, PD-1 expression effectively distinguishes exhaustion stages in CD8+ T cells. PD-1Int cells found in tumors, JTs, and TDLNs represent a promising therapeutic target for cancer immunotherapy.
    Keywords:  Breast cancer; CD8+ T cells; PD-1; draining lymph nodes; exhaustion
    DOI:  https://doi.org/10.1080/2162402X.2025.2502354
  14. Radiother Oncol. 2025 May 11. pii: S0167-8140(25)00227-0. [Epub ahead of print]208 110932
    TIGIT blockade increases efficacy of PD-1 blockade combined with radiation therapy in triple-negative breast cancer model.
    Seongmin Kim, Seung Hyuck Jeon, Yoomin Kim, Nawon Park, In Ah Kim.
       BACKGROUND AND PURPOSE: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) suppresses functions of CD8+ T cells, and radiation therapy (RT) induces stimulation of regulatory T cells (Tregs), thereby limiting antitumor efficacy. This study aims to investigate the role of TIGIT in the immunosuppressive tumor environment and evaluate the potential of TIGIT blockade (αTIGIT) to enhance antitumor immune responses.
    METHODS: We analyzed public transcriptomic data to identify the expression patterns of TIGIT on T cells in breast cancer and its prognostic impact. In addition, a murine TNBC model was utilized to evaluate the effects of αPD-1, local RT, and αTIGIT. T cells in tumors, tumor-draining lymph nodes (TdLNs), and the spleen were analyzed to assess the antitumor immune responses upon the treatments.
    RESULTS: The analysis revealed that TIGIT is predominantly expressed on T cells within breast cancer, and the expression of TIGIT was associated with poor outcomes in TNBC patients. In the murine model, the combination of αPD-1 and RT increased TIGIT+CD226+CD8+ TILs, which are crucial for the efficacy of αTIGIT. Adding αTIGIT to αPD-1 and RT (αPD-1/RT) resulted in a synergistic antitumor effect, which was accompanied by increased infiltration of CD8+ TILs in both irradiated and nonirradiated tumors by the triple combination therapy compared to αPD-1/RT. The triple combination therapy also resulted in a less exhausted phenotype among CD8+ TILs and increased the proliferation of splenic CD8+ T cells. Moreover, αTIGIT significantly reduced Tregs in tumors, TdLNs, and the spleen when combined with αPD-1/RT.
    CONCLUSION: αTIGIT exhibits synergistic effects when added to αPD-1/RT by increasing the infiltration and activation of CD8+ TILs while reducing Tregs. The study suggests that αTIGIT could be an effective strategy to enhance the antitumor efficacy of αPD-1 and RT in TNBC.
    Keywords:  Breast cancer; PD-1 blockade; Radiotherapy; T cell responses; TIGIT blockade
    DOI:  https://doi.org/10.1016/j.radonc.2025.110932
  15. Nanotechnology. 2025 May 16. 36(22):
    mRNA lipid nanoparticles in CAR-T therapy: a novel strategy to improve efficacy.
    Zengkai Zhao, Mingmei Li, Xiang Zheng, Pengli Gao, Chenlu Huang, Qingyu Yu, Limin Jin, Linhua Zhang, Dunwan Zhu, Fangzhou Li.
      Chimeric antigen receptor T cells (CAR-T) immunotherapy has achieved remarkable progress in the treatment of hematological malignancies. However, it encounters challenges including complex manufacturing processes, high cost, and safety issues. Lipid nanoparticle (LNP) technology, as an advanced gene delivery platform, offers significant advancements to CAR-T therapy through its high efficiency, low immunogenicity, and safety. LNP enablein vivoproduction of CAR-T cells, thereby improving delivery efficiency, reducing the risks of immunogenicity and insertional mutations, simplifying the production process and reducing costs. The scalability and rapid optimization ability of LNP position them as promising candidates for CAR-T cell production. LNP technology is expected to further promote the development of CAR-T immunotherapy and provide safer and more economical treatment options. Therefore, this paper aims to provide a comprehensive and systematic review of the application of LNP in CAR-T therapy. In this review, we initially outline the fundamental design, process, and current challenges of CAR-T therapy. Subsequently, we present the characteristics of LNP, their advantages as a gene delivery vectors, and how they improve the efficacy of CAR-T therapy. Finally, we summarize the current research landscape of LNP applications in CAR-T therapy. This includes enhancingin vitrotransfection of T cells, programming T cellsin situ, facilitating T-cell activation, alleviating the side effects of CAR-T therapy, and combining CAR-T therapy with other immunotherapies. These advancements will aid in the design of mRNA delivery systems based on LNP, thereby promoting the development of CAR-T therapy.
    Keywords:  CAR-T; immunotherapy; lipid nanoparticles; mRNA delivery
    DOI:  https://doi.org/10.1088/1361-6528/add482
  16. Front Immunol. 2025 ;16 1549229
    In vivo RNAi screen and validation reveals Ngp, Hba-a1, and S100a8 as novel inhibitory targets on T lymphocytes in liver cancer.
    Inga Hochnadel, Lisa Hoenicke, Nataliia Petriv, Huizhen Suo, Lothar Groebe, Chantal Olijnik, Nina Bondarenko, Juan C Alfonso, Michael Jarek, Ruibing Shi, Andreas Jeron, Kai Timrott, Tatjana Hirsch, Nils Jedicke, Dunja Bruder, Frank Klawonn, Ralf Lichtinghagen, Robert Geffers, Henrike Lenzen, Michael P Manns, Tetyana Yevsa.
       Background: Hepatocellular carcinoma (HCC) represents the third deadliest cancer worldwide with limited treatment options. Immune checkpoint inhibitors (ICIs) have revolutionized HCC therapy, but immune suppression within the tumor microenvironment remains a major challenge. Therefore, in this study, we aimed to define novel ICI molecules arising on T cells during aggressive HCC development.
    Methods: Using autochthonous HCC models, we performed microarray analyses followed by in vivo RNA interference screen and identified several new ICI molecules on CD4 and CD8 T lymphocytes in HCC-bearing mice. Short hairpin RNA (shRNA)-mediated knockdown of the ICI molecules was performed to validate their functional role in T cell activity and survival of HCC-bearing mice. Finally, we searched for the presence of the defined ICI molecules in HCC patients.
    Results: We identified neutrophilic granule protein (Ngp), hemoglobin subunit alpha-1 (Hba-a1), and S100 calcium-binding protein a8 (S100a8) as novel inhibitory molecules of T cells in HCC. The specific shRNA-based knockdown of these inhibitory targets was safe, led to a downregulation of classical ICI molecules (PD-1, PD-L1, 4-1BBL, CD160), and kept liver parameters under control in murine HCC. Besides, we detected upregulation of S100A8 and S100A9 in blood and liver tissues in HCC patients, supporting their clinical relevance.
    Conclusion: The obtained results pave the way for the use of the newly defined ICI molecules Ngp, Hba-a1, and S100a8 as novel immunotherapeutic targets in further preclinical and clinical studies in HCC patients.
    Keywords:  RNA interference screen; T lymphocytes; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1549229
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