OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-08-16DOI: 10.1080/2162402X.2025.2547271
Nora Möhn, Emily Narten, Laura Duzzi, Janin Thomas, Lea Grote-Levi, Gernot Beutel, Tabea Fröhlich, Benjamin-Alexander Bollmann, Thomas Wirth, Imke von Wasielewski, Ralf Gutzmer, Florian Heidel, Frank Pessler, Walter Zobl, Sven Schuchardt, Philipp Ivanyi, Sandra Nay, Thomas Skripuletz
{"title":"Low triglyceride levels are associated with increased risk of immune-related adverse events in patients receiving immune checkpoint inhibitors.","authors":"Nora Möhn, Emily Narten, Laura Duzzi, Janin Thomas, Lea Grote-Levi, Gernot Beutel, Tabea Fröhlich, Benjamin-Alexander Bollmann, Thomas Wirth, Imke von Wasielewski, Ralf Gutzmer, Florian Heidel, Frank Pessler, Walter Zobl, Sven Schuchardt, Philipp Ivanyi, Sandra Nay, Thomas Skripuletz","doi":"10.1080/2162402X.2025.2547271","DOIUrl":"10.1080/2162402X.2025.2547271","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy by enhancing anti-tumor immune responses, yet their use can lead to immune-related adverse events (irAE), including neurological complications. Despite their clinical relevance, predictive biomarkers for irAE remain scarce, and early identification of at-risk patients is a major unmet need. In this prospective study, 200 patients undergoing ICI therapy were enrolled, of whom 59 underwent longitudinal metabolomic profiling at baseline, three months, and six months. Thirty-two patients who developed irAE were compared to 27 age- and sex-matched individuals without irAE. Multivariate analyses, including Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA), revealed distinct metabolomic signatures differentiating the two groups. Notably, baseline levels of triglyceride 20:0_34:1 were significantly lower in irAE(+) patients. In female patients, additional triglyceride species-20:1_34:2, 20:2_34:2, and 20:2_34:3-were also reduced prior to therapy and showed increases within three months of ICI initiation. These findings suggest that specific triglyceride species may serve as early biomarkers for irAE risk, particularly in female patients. The observed dynamic changes point to a potential link between lipid metabolism and immune-related toxicity, supporting the integration of metabolomic profiling into future strategies for risk stratification and personalized monitoring in cancer immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2547271"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-09-25DOI: 10.1080/2162402X.2025.2563099
María Burón, Anne Etxebarria, Maite Álvarez, Irene Romayor, Cristina Eguizabal
{"title":"Natural killer cells in adoptive cell therapy: current landscape of genetic engineering strategies.","authors":"María Burón, Anne Etxebarria, Maite Álvarez, Irene Romayor, Cristina Eguizabal","doi":"10.1080/2162402X.2025.2563099","DOIUrl":"10.1080/2162402X.2025.2563099","url":null,"abstract":"<p><p>Among adoptive cell-based immunotherapies, chimeric antigen receptor (CAR) therapy has shown promising results in cancer treatment. Treatment with CAR-T cells has produced remarkable clinical responses, especially in cases of relapsed and refractory leukemia and lymphoma. However, CAR-T cell therapy still presents several limitations, including some safety concerns related to neurotoxicity and aggressive inflammatory responses. As an alternative to T-cells, natural killer (NK) cells have been developed as an attractive option for efficient cancer immunotherapy. As they do not express T cell receptor (TCR), NK cell-based therapies are not associated with cytokine release syndrome (CRS) or graft versus host disease (GvHD), which enables a safer therapy and the ability to generate an allogeneic \"off-the-shelf\" product. Despite the innate cytotoxic activity of NK cells against malignant cells, the therapeutic application of unmodified NK cells has been compromised by the inhibitory tumor microenvironment (TME), which is responsible for poor cell expansion, inactivation, insufficient tumor infiltration, and limited in vivo persistence, leading to the dysfunction of NK cells after infusion. Advances in the genetic modification of NK cells can address some of these limitations and improve their therapeutic efficacy. In this review, we describe the advances in the development of engineered NK cells for cancer immunotherapy. As such, we provide an overview of recent viral and non-viral approaches for the genetic modification of NK cells. We also discuss their current clinical status in the field of immunotherapy, and their use in other clinical applications.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2563099"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CAR-T cell engineered with TCR-like antibody specific for HBV surface antigen epitope E183-91/HLA-A *0201 exhibit potent activity against HBV-HCC.","authors":"Fengling Wang, Jiaqian Li, Yong Huang, Feiyang Yan, Haozhan Gao, Weilin Zhou, Xinyu Gu, Dan Li, Yalan Zhang, Jing Li, Yuening Yang, Jiangping Yang, Mengxi Zhang, Jinrong Yang, Shimao Qi, Wei Wang","doi":"10.1080/2162402X.2025.2546404","DOIUrl":"10.1080/2162402X.2025.2546404","url":null,"abstract":"<p><p>CAR-T cell therapy demonstrates significant efficacy in hematologic malignancies, with target selection critically determining therapeutic outcomes. However, the available tumor surface antigens are limited, especially in the treatment of solid tumors. A potential solution to overcome this limitation entails employing antibodies recognizing peptide-major histocompatibility complex (pMHC) structures, enabling CAR-T cell to detect intracellular tumor antigens through a T cell receptor (TCR)-like recognition mechanism. This study focuses on HBV-associated hepatocellular carcinoma (HBV-HCC), where HBV DNA integration into the host genome generates specific viral antigen epitopes presented by MHC class I molecules, representing attractive targets for CAR-T cell therapy. We engineered CAR-T cells with a TCR-like antibody (HBs183 CAR-T) specific for the immunodominant HBV envelope epitope Env183-191 presented by HLA-A *0201, and evaluated the antigen-specific cytotoxicity and safety profile of the CAR-T cells through in vitro functional assays and in vivo evaluation in heterogenous tumor models (subcutaneous and intraperitoneal xenografts). Our research provides a reference for CAR-T cell therapy targeting intracellular antigens, particularly specific antigens derived from viral infections, as targets for CAR-T treatment, and offers a preliminary concept validation for the CAR-T treatment of HBV-HCC tumors.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2546404"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-07-28DOI: 10.1080/2162402X.2025.2539442
Yu-Chen Shi, Qingling An, Na Tang, Yong-Qiang Zhang, Shu-Qiao Xing, Fan Song, Xiao-Qiang Li
{"title":"Inhibition of FAK promotes pancreatic cancer immunotherapy by mediating CXCL10 secretion to enhance CD8<sup>+</sup> T cell infiltration.","authors":"Yu-Chen Shi, Qingling An, Na Tang, Yong-Qiang Zhang, Shu-Qiao Xing, Fan Song, Xiao-Qiang Li","doi":"10.1080/2162402X.2025.2539442","DOIUrl":"10.1080/2162402X.2025.2539442","url":null,"abstract":"<p><p>Immunotherapy has demonstrated potential in treating various malignant tumors, but its efficacy in pancreatic cancer (PC) remains limited, possibly due to the dense stromal components and immunosuppressive microenvironment of PC. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a crucial role in the tumor microenvironment and intracellular signaling pathways. However, the specific role of FAK in the development and progression of PC, as well as its regulatory mechanisms on the tumor immune microenvironment (TIM), are still not fully understood. In this study, we analyzed single-cell sequencing datasets and clinical specimens to evaluate the role of FAK in the immune response of PC. We verified the impact of FAK alterations on CD8<sup>+</sup> T cell infiltration using a co-culture system of patient-derived organoids (PDO) and immune cells. Additionally, mouse PC models and dual humanized models are established to investigate the in vivo function of FAK and the potential of its inhibitors for immunotherapy. Our results demonstrate that FAK is associated with the immunosuppressive microenvironment in PC. Inhibiting FAK enhances CD8<sup>+</sup> T cell infiltration by promoting CXCL10 secretion in PC. Moreover, FAK inhibitors exhibit a synergistic anti-tumor effect when combined with immune checkpoint inhibitors. This study explores the potential of FAK as a therapeutic target, particularly its role in modulating TIM, thereby providing new research directions for the treatment of PC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2539442"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144734442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-07-15DOI: 10.1080/2162402X.2025.2533488
Oliver Kepp, Guido Kroemer
{"title":"Immunogenic cell death and bystander killing: expanding the therapeutic potential of modern antibody-drug conjugates.","authors":"Oliver Kepp, Guido Kroemer","doi":"10.1080/2162402X.2025.2533488","DOIUrl":"10.1080/2162402X.2025.2533488","url":null,"abstract":"<p><p>HER3-DXd and T-DXd are antibody-drug conjugates (ADCs) that induce immunogenic cell death and bystander killing, enhancing antitumor immunity beyond target-specific cytotoxicity. These findings highlight novel mechanisms that can overcome antigen heterogeneity and suggest opportunities for improving ADC design and therapeutic synergy through informed combination with immunotherapies.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2533488"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment.","authors":"Zuhairah Binte Hanafi, Yu Mei, Huey Yee Teo, Ying Zhu, Chew Chin Yong Lionel, Jing Wen Chiu, Jinhua Lu, Haiyan Liu","doi":"10.1080/2162402X.2025.2451444","DOIUrl":"10.1080/2162402X.2025.2451444","url":null,"abstract":"<p><p>Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2451444"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-04-15DOI: 10.1080/2162402X.2025.2492932
Fabrice Barlesi, Adrien Dixmier, Didier Debieuvre, Christophe Raspaud, Jean-Bernard Auliac, Nicolas Benoit, Pierre Bombaron, Denis Moro-Sibilot, Bernard Asselain, Clarisse Audigier-Valette, Florence Brellier, François-Emery Cotté, Yaacoub Khalife, Maurice Pérol
{"title":"Final 3-year results from the EVIDENS study, an observational study of nivolumab in non-small cell lung cancer.","authors":"Fabrice Barlesi, Adrien Dixmier, Didier Debieuvre, Christophe Raspaud, Jean-Bernard Auliac, Nicolas Benoit, Pierre Bombaron, Denis Moro-Sibilot, Bernard Asselain, Clarisse Audigier-Valette, Florence Brellier, François-Emery Cotté, Yaacoub Khalife, Maurice Pérol","doi":"10.1080/2162402X.2025.2492932","DOIUrl":"https://doi.org/10.1080/2162402X.2025.2492932","url":null,"abstract":"<p><p>EVIDENS was a prospective, non-interventional, longitudinal study conducted in non-small cell lung cancer (NSCLC) patients receiving nivolumab in France. It recruited adults with pathologically confirmed NSCLC who initiated nivolumab between October 2016 and November 2017; the final results are reported here. Primary outcomes included baseline characteristics and 36-month overall survival (OS). Secondary outcomes included progression free survival (PFS), objective response rate (ORR), safety and health-related quality of life (HRQoL; assessed regardless of nivolumab continuation or interruption). Overall, 1423 patients were included in the analysis population (median age 66 years; non-squamous histology 69.1%; stage IV disease 91.5%; brain metastases 19.9%). Almost all patients (99.7%) had received prior chemotherapy, and most patients received nivolumab as second-line (73.5%) or later (26.1%) therapy. The 36-month OS rate was 19.7% (95% confidence interval [CI] 17.5-22.0); OS was significantly shorter in patients with squamous versus non-squamous tumors (9.8 [95% CI 8.6-11.2] months vs 11.8 [95% CI 10.2-13.2] months; <i>p</i> = 0.005). The 36-month PFS rate was 8.8% (95% CI 7.3-10.4). The 12-month investigator-assessed best ORR in the overall population was 20.4%. Eastern Cooperative Oncology Group performance status, smoking status, tumor histology, disease stage and liver metastasis independently predicted survival. Grade 3 and 4 treatment-related adverse events were reported in 8.0% and 0.8% of patients, respectively; eight treatment-related deaths occurred (0.005%). HRQoL was maintained with slight improvement throughout the study, without statistical significance. These results confirm that the real-world effectiveness and safety of nivolumab in these patients is similar to that observed in clinical trials.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2492932"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-05-12DOI: 10.1080/2162402X.2025.2502354
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
{"title":"CD8<sup>+</sup> T cells in breast cancer tumors and draining lymph nodes: PD-1 levels, effector functions and prognostic relevance.","authors":"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","doi":"10.1080/2162402X.2025.2502354","DOIUrl":"10.1080/2162402X.2025.2502354","url":null,"abstract":"<p><p>CD8<sup>+</sup> T cells shape the antitumor immune response. Here, we evaluated CD8<sup>+</sup> 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<sup>+</sup> T cells in tumors, juxtatumoral tissues (JTs), and tumor-draining lymph nodes (TDLNs). Terminal exhausted CD8<sup>+</sup> T cells (PD-1<sup>High</sup> CD8<sup>+</sup>) were predominant in tumors and nearly absent in other tissues. However, in all tissues evaluated, most CD8<sup>+</sup> T cells exhibited a pre-exhausted phenotype (PD-1<sup>Int</sup> CD8<sup>+</sup>) or did not express PD-1. PD-1<sup>High</sup> and PD-1<sup>Int</sup> CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> terminal exhaustion and a CD8<sup>+</sup> 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<sup>+</sup> T cells. PD-1<sup>Int</sup> cells found in tumors, JTs, and TDLNs represent a promising therapeutic target for cancer immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2502354"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-07-13DOI: 10.1080/2162402X.2025.2532662
Annina Kurzay, Sara Fresnillo Saló, Anne Rahbech, Tina Seremet, Cecilie Oelvang Madsen, Christopher Aled Chamberlain, Emilie Bülow Jensen, Viet Thy Luu, Özcan Met, Marlies J W Peeters, Per Thor Straten
{"title":"ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality.","authors":"Annina Kurzay, Sara Fresnillo Saló, Anne Rahbech, Tina Seremet, Cecilie Oelvang Madsen, Christopher Aled Chamberlain, Emilie Bülow Jensen, Viet Thy Luu, Özcan Met, Marlies J W Peeters, Per Thor Straten","doi":"10.1080/2162402X.2025.2532662","DOIUrl":"10.1080/2162402X.2025.2532662","url":null,"abstract":"<p><p>Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion - features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2532662"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncoimmunologyPub Date : 2025-12-01Epub Date: 2025-09-25DOI: 10.1080/2162402X.2025.2562210
Ana L Portillo, Misaal Mehboob, Genesis Snyder, Adnan Moinuddin, Tyrah M Ritchie, Elizabeth Balint, Allyson E Moore, Mohammadamin Sookhaklari, Jonathan L Bramson, Dean A Lee, Meisam Naeimi Kararoudi, Ali A Ashkar
{"title":"IL-21-reprogrammed Vδ1 T cells exert killing against solid tumors which is enhanced by CAR arming for off-the-shelf immunotherapy.","authors":"Ana L Portillo, Misaal Mehboob, Genesis Snyder, Adnan Moinuddin, Tyrah M Ritchie, Elizabeth Balint, Allyson E Moore, Mohammadamin Sookhaklari, Jonathan L Bramson, Dean A Lee, Meisam Naeimi Kararoudi, Ali A Ashkar","doi":"10.1080/2162402X.2025.2562210","DOIUrl":"10.1080/2162402X.2025.2562210","url":null,"abstract":"<p><p>Cancer cell therapies have primarily focused on engineering autologous αβ T cells with chimeric antigen receptors (CARs), achieving clinical success against hematologic malignancies. However, their effectiveness against solid tumors is limited by challenges such as antigen escape, suppression by the metabolically hostile tumor microenvironment (TME), and manufacturing difficulties. γδ T cells are unconventional T cells with innate tumor-targeting capabilities independent of MHC class I, making them an emerging candidate for allogeneic cell therapy. While the Vδ1 T cell subset has shown promising anti-tumor killing their clinical application has been hindered by difficulties in achieving robust expansion for therapeutic use. Here, we evaluated the potential of K562 feeder cells expressing membrane-bound IL-21 (K562-mb-IL-21) to expand and activate γδ T cells from peripheral blood. Our findings show that this method preferentially expands Vδ1 T cells, resulting in an activated phenotype characterized by enhanced expression of NK cell activation receptors, innate cytotoxicity against breast and ovarian cancer cells, and sustained metabolic function in patient-derived ascites TME. When engineered with a CAR, Vδ1 T cells exhibited further enhanced anti-tumor efficacy in an immunodeficient NRG xenograft model of human ovarian cancer. These findings highlight K562-mb-IL-21 expanded peripheral blood Vδ1 T cells as a promising 'off-the-shelf' allogeneic therapy for solid tumors.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2562210"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}