Oncoimmunology最新文献

{"title":"Selective serotonin reuptake inhibitors enhance cancer immunosurveillance by pleiotropic mechanisms.","authors":"Karla Alvarez-Valadez, Guido Kroemer, Mojgan Djavaheri-Mergny","doi":"10.1080/2162402X.2025.2564734","DOIUrl":"10.1080/2162402X.2025.2564734","url":null,"abstract":"<p><p>In a recent paper published in <i>Cell</i>, Li et al. suggest that selective serotonin reuptake inhibitors (SSRIs) antidepressants act on serotonin transporters on CD8⁺ T cells to enhance antitumor immunity. Beyond this mechanism, SSRIs can act on malignant cells, as well as on other immune cells, to improve cancer immunosurveillance.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2564734"},"PeriodicalIF":6.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200658","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":"MERTK inhibition improves therapeutic efficacy of immune checkpoint inhibitors in hepatocellular carcinoma.","authors":"Diana Llopiz, Leyre Silva, Marta Ruiz, Carla Castro-Alejos, Belen Aparicio, Lucia Vegas, Stefany Infante, Eva Santamaria, Pablo Sarobe","doi":"10.1080/2162402X.2025.2473165","DOIUrl":"10.1080/2162402X.2025.2473165","url":null,"abstract":"<p><p>Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2473165"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543649","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":"XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial.","authors":"Maggie J Phillips, Olatunji B Alese, Natalie K Horvat, Emily Greene, Olumide B Gbolahan, Kathleen Coleman, Deon B Doxie, Vaunita Parihar, Zaid K Mahdi, Ashley McCook-Veal, Jeffrey M Switchenko, Maria Diab, Cameron J Herting, Chrystal M Paulos, Bassel F El-Rayes, Gregory B Lesinski","doi":"10.1080/2162402X.2025.2475620","DOIUrl":"10.1080/2162402X.2025.2475620","url":null,"abstract":"<p><p>We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients. Comprehensive analyses of plasma cytokines, peripheral blood mononuclear cells (PBMCs), and spatial immune cell patterns in liver biopsies were performed to identify unique immune signatures resulting from the combined therapy. The combination of pembrolizumab and XL888 proved to be safe and feasible, with a subset of patients achieving stable disease, although no objective responses were observed in this heavily pre-treated population. Correlative studies revealed immunomodulatory effects in tumors and circulation, including a reduction in IL6⁺ cells and macrophages (CD68⁺) within metastatic liver tissue, alterations in blood CD3⁺ cells, and upregulation of numerous inflammatory plasma cytokines. These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2475620"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626510","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":"Induction of cell death in malignant cells and regulatory T cells in the tumor microenvironment by targeting CD137.","authors":"Rui Sun, Kang Yi Lee, Yu Mei, Emily Nickles, Jia Le Lin, Runze Xia, Haiyan Liu, Herbert Schwarz","doi":"10.1080/2162402X.2024.2443265","DOIUrl":"https://doi.org/10.1080/2162402X.2024.2443265","url":null,"abstract":"<p><p>Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers. Further, CD137 is expressed by malignant cells of certain cancers, making it a potential target for tumor immunotherapy. Here, we report the development of a fully human anti-human CD137 antibody of the IgG1 isotype, clone P1A1, that induces antibody-dependent cell-mediated cytotoxicity (ADCC) in CD137⁺ Tregs and cancer cells. P1A1 cross-reacts with murine CD137 which allowed testing murine chimeric P1A1 in syngeneic murine tumor models where P1A1 significantly reduced the number of CD137⁺ Tregs and inhibited tumor growth in a murine hepatocellular carcinoma (HCC) and a melanoma lung metastasis model. P1A1 can also be internalized thus enabling it as a carrier for drugs to target CD137⁺ Tregs and cancer cells. These anti-cancer properties suggest a translation of P1A1 to human immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2443265"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating cytokine associations with clinical outcomes in melanoma patients treated with combination nivolumab plus ipilimumab.","authors":"Jiajia Chen, Giuseppe Tarantino, Mariano Severgnini, Joanna Baginska, Anita Giobbie-Hurder, Jason L Weirather, Michael Manos, Janice D Russell, Kathleen L Pfaff, Scott J Rodig, Amy Y Huang, Ryan Brennick, Matthew Nazzaro, Emma Hathaway, Marta Holovatska, Claire Manuszak, Srinika Ranasinghe, David Liu, F Stephen Hodi","doi":"10.1080/2162402X.2024.2432723","DOIUrl":"10.1080/2162402X.2024.2432723","url":null,"abstract":"<p><p>Nivolumab plus ipilimumab (aCTLA-4/aPD-1) combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. We hypothesized that circulating cytokines and peripheral white blood cells may predict response to therapy and evaluated 15 cytokines and complete blood counts (CBC with differentials) from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. Clinical endpoints evaluated included durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). A parsimonious predictive model was developed to identify cytokines predictors of response to combination therapy. In this study, we found that pre-treatment, patients with DCB had higher IL-23, lower CXCL6, and lower IL-10 levels. Lower NLR one month after starting therapy predicted better PFS and OS, primarily driven by an increase in absolute lymphocytes. A multivariate model demonstrated that baseline CXCL6, IL-10, IL-23 were independent predictors of therapy response, and the combined model has reached an area under the curve (AUC) of 0.79 in prediction of response to combination therapy. Our study identified baseline CXCL6, IL-23, and IL-10 as predictors of response to aCTLA4/aPD1 combination therapy among patients with metastatic melanoma. This study also provides a framework for identifying patients who are likely to respond to combination ICB, as well as a subset of patients with high risk of developing resistance and are thus in need of alternative therapeutic options, such as clinical trials.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2432723"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856325","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":"Mitochondrial DNA transfer between malignant cells and T lymphocytes shapes the cancer-immunity dialogue.","authors":"Liwei Zhao, Peng Liu, Oliver Kepp, Guido Kroemer","doi":"10.1080/2162402X.2025.2512109","DOIUrl":"10.1080/2162402X.2025.2512109","url":null,"abstract":"<p><p>Nonmutated mitochondrial DNA (mtDNA) from T lymphocytes can be incorporated into cancer cells bearing mutated mtDNA to repair their bioenergetic deficiency. However, a recent paper by Ikeda et al. indicates that mutated mtDNA from malignant cells can also be transferred into tumor-infiltrating T lymphocytes to subvert their function in cancer immunosurveillance.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2512109"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163151","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":"Utilization of universal-targeting mSA2 CAR-T cells for the treatment of glioblastoma.","authors":"Alexandros Kourtesakis, Eileen Bailey, Hiu Nam Hannah Chow, Hannah Rohdjeß, Normann Mussnig, Dennis Alexander Agardy, Dirk Carsten Frieder Hoffmann, Yu-Chan Chih, Rainer Will, Leon Kaulen, Melissa Hahn, Robin Wagener, Denise Reibold, Sonja Pusch, Felix Sahm, Tim Sauer, Michael Schmitt, Lukas Bunse, Michael Platten, Wolfgang Wick, Tobias Kessler","doi":"10.1080/2162402X.2025.2518631","DOIUrl":"10.1080/2162402X.2025.2518631","url":null,"abstract":"<p><p>Glioblastoma (GB) remains refractory to chimeric antigen receptor (CAR)-T cell therapy, mainly attributed to tumor heterogeneity and antigen escape. CAR-T cells utilizing monomeric streptavidin-2 (mSA2) instead of a traditional target binding domain, bind biotinylated antibodies and can be directed to variable targets to mediate anti-tumor effects. Although such an approach might circumvent the aforementioned challenges, the potential of mSA2 CAR-T cells for brain tumor treatment remains unexplored. In this study, we generated mSA2 CAR-T cells and tested their efficacy against GB by tailoring their specificity toward GB-associated markers CD276, EPHA2, CD70 and IL13Ra2. <i>In vitro</i>, mSA2 CAR-T cells specifically recognized multiple primary GB cell lines in a target- and biotinylated antibody-dependent manner. Moreover, in heterogenous tumor environments, mSA2 CAR-T cells simultaneously targeted multiple subpopulations, guided by combinations of biotinylated antibodies, indicating their potential to address tumor heterogeneity. Finally, the mSA2 CAR-T cell-mediated anti-tumor functions were demonstrated <i>in vivo</i>. Immunocompromised mice orthotopically implanted with CD70⁺ or CD276⁺ GB cells and treated with mSA2 CAR-T cells pre-armed with antibodies against these two antigens exhibited control of tumor growth and induction of GB cell apoptosis after therapy. Taken together, our study suggests that antibody-guided mSA2 CAR-T cells can target potentially any surface GB-related antigen both <i>in vitro</i> and <i>in vivo</i>, either univalently or multivalently, with underlined clinical implications.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2518631"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303377","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":"Pan-cancer single cell transcriptomic clustering reveals heterogeneous CD8⁺ exhausted T cell populations with different immune checkpoint inhibitor responses.","authors":"Rui Mu, Rasha Barakat, David H Gutmann","doi":"10.1080/2162402X.2025.2540504","DOIUrl":"10.1080/2162402X.2025.2540504","url":null,"abstract":"<p><p>In most cancers, T lymphocytes comprise an essential cellular component of the non-neoplastic microenvironment, where they have the capacity to both suppress and support tumor growth. One specialized T lymphocyte population is the CD8⁺ exhausted T cell, which has been intensely studied as an actionable therapeutic target. Unfortunately, there is currently no uniformly accepted classification scheme for these specialized T cells. To provide a potential model for classifying CD8⁺ exhausted T cells, we leveraged single cell transcriptomic analysis of a diverse collection of both human (<i>n</i> = 8) and mouse (<i>n</i> = 4) cancers to identify unique subpopulations shared across tumor types and species. By integrating data from both human and mouse cancer studies, as well as previously described CD8⁺ exhausted T cell subsets, we provide an integrated framework to characterize the heterogeneity of exhausted CD8⁺ T cells. As such, one of these subpopulations (cluster C1) increases following immune checkpoint inhibitor treatment in the setting of cancer in mice and patients. Taken together, this proposed classification scheme may be useful for the design and interpretation of current and future immune-based therapy studies.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2540504"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776677","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":"A preclinical model for the identification of therapeutically active transgenes in local cancer immunotherapy.","authors":"Arne Menze, Dmitrij Ostroumov, Hans Heinrich Wedemeyer, Valery Volk, Friedrich Feuerhake, Florian Kühnel, Thomas Christian Wirth","doi":"10.1080/2162402X.2025.2543620","DOIUrl":"https://doi.org/10.1080/2162402X.2025.2543620","url":null,"abstract":"<p><p>The efficacy of systemic immunotherapies is limited for poorly immunogenic tumors which suppress T cell priming and tumor infiltration. Modern antigen carriers including viral vectors and messenger RNA/lipid nanoparticle (LNP) combinations have renewed the interest in local immunotherapy due to their ability to express multiple transgene constructs simultaneously. The identification of therapeutically active combinations, however, is hampered by the lack of preclinical models to rapidly express and evaluate transgenes combinations <i>in vivo</i>. To enable empirical testing of immunogenic transgenes, we have combined a doxycycline-inducible expression system with flow cytometry and multiplex immunohistochemistry imaging. In animal models of liver and colon cancer, we demonstrate that the impact of a single transgene on the immune milieu is limited and heavily dependent on the studied tumor entity. Compared to single transgenes, transgene combinations induced more complex and only partially predictable alterations in the tumor micromilieu but strongly enhanced therapeutic efficacy. By combining expression of transgenes with impact on antigen-presenting cells and T cells, we identified a combination of IL-12, CXCL9 and FLT3L as the most promising combinatorial approach, resulting in complete tumor remissions in mice. Taken together, we demonstrate the ability of our preclinical model to identify therapeutic transgene combinations for more efficacious locoregional immunotherapy of solid tumors.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2543620"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An immunological mechanism of resistance to CDK4/6 inhibitors in HR⁺ breast cancer.","authors":"Claudia Galassi, Giulia Petroni, Simon R V Knott, Lorenzo Galluzzi","doi":"10.1080/2162402X.2025.2520269","DOIUrl":"10.1080/2162402X.2025.2520269","url":null,"abstract":"<p><p>CDK4/6 inhibitors are central to the clinical management of HR⁺HER2^- breast cancer. We have recently demonstrated that immunosuppressive, IL17-secreting γδ T cells recruited to the tumor microenvironment by a CCL2-dependent mechanism upon CDK4/6 inhibition can repolarize tumor-associated macrophages toward a CX3CR1⁺ phenotype associated with resistance to therapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2520269"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638475","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}