Oncoimmunology最新文献

{"title":"Gasdermin E links tumor cell-intrinsic nucleic acid signaling to proinflammatory cell death for successful checkpoint inhibitor cancer immunotherapy.","authors":"Stefan Enssle, Anna Sax, Peter May, Nadia El Khawanky, Nardine Soliman, Markus Perl, Julius C Enssle, Karsten Krey, Jürgen Ruland, Andreas Pichlmair, Florian Bassermann, Hendrik Poeck, Simon Heidegger","doi":"10.1080/2162402X.2025.2504244","DOIUrl":"https://doi.org/10.1080/2162402X.2025.2504244","url":null,"abstract":"<p><p>Durable clinical responses to immune checkpoint inhibitors (ICI) are limited to a minority of patients, and molecular pathways that modulate their efficacy remain incompletely defined. We have recently shown that activation of the innate RNA-sensing receptor RIG-I and associated apoptotic tumor cell death can facilitate tumor immunosurveillance and -therapy, but the mechanism that drives its immunogenicity remained unclear. We here show that intratumoral activity of the pore-forming protein gasdermin E (GSDME) links active RIG-I signaling and apoptotic cell death in tumor cells to inflammatory pyroptosis. Activation of tumor-intrinsic RIG‑I triggered cleavage of GSDME, pore formation, loss of cell membrane integrity and leakage of cytosolic components from dying tumor cells. Tumor antigen cross-presentation by dendritic cells and subsequent expansion of cytotoxic T cells strongly relied on tumor-intrinsic GSDME activity. In preclinical murine cancer models, defective GSDME signaling rendered tumors resistant to ICI therapy. Epigenetic reprogramming with upregulation of <i>Gdsme</i> enhanced the susceptibility of tumor cells to inflammatory cell death and immunotherapy. In humans, transcriptome analysis of melanoma samples showed strong correlation between genetic activity of the RIG-I and pyroptosis pathways. In melanoma patients, high transcriptional activity of a pyroptosis gene set was associated with prolonged survival and beneficial response to ICI therapy. In summary, our data show that GSDME links RIG-I and apoptotic signaling to inflammatory cell death, thereby driving its immunogenicity and responsiveness to ICI. A deeper understanding of these pathways may allow for the development of novel combined modality approaches to improve ICI treatment responses in cancer patients.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2504244"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081484","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":"Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy.","authors":"Kengo Tanigawa, William L Redmond","doi":"10.1080/2162402X.2025.2452654","DOIUrl":"10.1080/2162402X.2025.2452654","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has significantly improved the survival for many patients with advanced malignancy. However, fewer than 50% of patients benefit from ICB, highlighting the need for more effective immunotherapy options. High-dose interleukin-2 (HD IL-2) immunotherapy, which is approved for patients with metastatic melanoma and renal cell carcinoma, stimulates CD8⁺ T cells and NK cells and can generate durable responses in a subset of patients. Moreover, HD IL-2 may have potential efficacy in patients whose disease has progressed following ICB and plays a vital role in expanding tumor-infiltrating lymphocyte (TIL) in TIL therapy. Despite its potential, the use of HD IL-2 is limited by severe toxicities such as hypotension and vascular leak syndrome. Additionally, only a few patients achieve a good outcome after HD IL-2 therapy. To address these challenges, numerous next-generation IL-2 receptor (IL-2 R) agonists have been developed to exhibit treatment effects while minimizing adverse events. This review will explore IL-2 biology, the clinical application of HD IL-2 therapy, and the development of novel IL-2 R agonists for cancer immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2452654"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984678","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":"Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade.","authors":"Pedro Rocha, Rafael Bach, Laura Masfarré, Sharia Hernandez, Nil Navarro-Gorro, Adrià Rossell, Xavier Villanueva, Mario Giner, Ignacio Sanchéz, Miguel Galindo, Raúl Del Rey-Vergara, Albert Iñañez, Beatriz Sanchéz-Espiridion, Wei Lu, Ariadna Acedo-Terrades, Pau Berenguer-Molins, Albert Sánchez-Font, Roberto Chalela, Victor Curull, Álvaro Taus, Max Hardy-Werbin, Mark Sausen, Andrew Georgiadis, James White, Jennifer B Jackson, Laura Moliner, Sergi Clavé, Beatriz Bellosillo, Ana Rovira, Ignacio Wistuba, Luisa M Solis Soto, Júlia Perera-Bel, Edurne Arriola","doi":"10.1080/2162402X.2025.2469377","DOIUrl":"10.1080/2162402X.2025.2469377","url":null,"abstract":"<p><strong>Introduction: </strong>Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.</p><p><strong>Methods: </strong>A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.</p><p><strong>Results: </strong>Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (<i>p</i> = 0.005) and higher incidence of irAEs (<i>p</i> = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (<i>p</i> < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (<i>p</i> < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (<i>p</i> < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.</p><p><strong>Conclusions: </strong>Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2469377"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484335","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":"Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells.","authors":"Meng Li, Di Li, Hai-Yun Wang, Weixin Zhang, Zhenjian Zhuo, Huiqin Guo, Jiabin Liu, Yue Zhuo, Jue Tang, Jing He, Lei Miao","doi":"10.1080/2162402X.2025.2460281","DOIUrl":"10.1080/2162402X.2025.2460281","url":null,"abstract":"<p><p>The exploration of therapeutic targets in neuroblastoma (NB), which needs more attempts, can benefit patients with high-risk NB. Based on metabolomic and transcriptomic data in mediastinal NB tissues, we found that the content of long-chain acylcarnitine (LCAC) was increased and positively associated with leptin expression in advanced NB. Leptin over-expression forced naïve CD4+ T cells to differentiate into Treg cells instead of Th17 cells, which benefited from NB cell proliferation, migration, and drug resistance. Mechanically, leptin in NB cells blunted the activity of carnitine palmitoyltransferase 2 (CPT2), the key enzyme for LCAC catabolism, by inhibiting sirtuin 3-mediated CPT2 deacetylation, which depresses oxidative phosphorylation (OXPHOS) for energy supply and increases lactic acid (LA) production from glycolysis to modulate CD4+ T cell differentiation. These findings highlight that excess leptin contributes to lipid metabolism dysfunction in NB cells and subsequently misdirects CD4+ T cell differentiation in tumor micro-environment (TME), indicating that targeting leptin could be a therapeutic strategy for retarding NB progression.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2460281"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190574","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":"Targeting the atypical chemokine receptor 2 (<i>Ackr2</i>) improves the benefit of anti-PD-1 immunotherapy in melanoma mouse model.","authors":"Muhammad Zaeem Noman, Martyna Szpakowska, Malina Xiao, Ruize Gao, Kris Van Moer, Akinchan Kumar, Markus Ollert, Guy Berchem, Andy Chevigné, Bassam Janji","doi":"10.1080/2162402X.2025.2494426","DOIUrl":"https://doi.org/10.1080/2162402X.2025.2494426","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) therapies, such as anti-PD-1, have transformed cancer treatment, but many patients do not respond due to a non-inflammatory tumor microenvironment (TME). Here, we investigated the impact of targeting Atypical Chemokine Receptor 2 (<i>ACKR2</i>), which scavenges key chemokines involved in immune cell recruitment, on the improvement of anti-PD-1-based therapy. In a melanoma mouse model, we demonstrated that <i>Ackr2</i> inhibition increases the release of proinflammatory chemokines CCL5 and CXCL10 and enhances the infiltration of NK cells, activated CD8+ and CD4+ effector T cells while reducing regulatory T cells (Tregs) in the TME. Targeting <i>Ackr2</i> led to tumor growth inhibition, improved survival, and enhanced response to anti-PD-1 therapy. In BRAF- and NRAS-mutant melanoma patients, low <i>ACKR2</i> expression or high CCL5/CXCL10 levels correlated with improved survival and higher CD8+ T cell markers. Targeting <i>ACKR2</i> represents a promising approach for developing combination therapies, particularly for 'cold' ICB resistant tumors.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2494426"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057794","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":"Glutamate promotes CCL2 expression to recruit tumor-associated macrophages by restraining EZH2-mediated histone methylation in hepatocellular carcinoma.","authors":"Jing Chen, Hong-Wei Sun, Run-Zheng Wang, Yun-Fei Zhang, Wen-Jiao Li, Yong-Kui Wang, Hao Wang, Miao-Miao Jia, Qing-Xia Xu, Hao Zhuang, Ning Xue","doi":"10.1080/2162402X.2025.2497172","DOIUrl":"https://doi.org/10.1080/2162402X.2025.2497172","url":null,"abstract":"<p><p>Glutamate is well-known as metabolite for maintaining the energy and redox homeostasis in cancer, moreover it is also the primary excitatory neurotransmitter in the central nervous system. However, whether glutamatergic signaling can regulate hepatocellular carcinoma (HCC) progression and the specific regulatory mechanisms are unknown. In the present study, we found that glutamate and its receptor NMDAR2B were significantly elevated in HCC patients, which predicts poor prognosis. Glutamate could upregulate CCL2 expression on hepatoma cells and further enhance the capability of tumor cells to recruit tumor-associated macrophages (TAMs). Mechanistically, glutamate could facilitate CCL2 expression through NMDAR pathway by decreasing the expression of EZH2, which regulates the H3K27me3 levels on the CCL2 promoter, rather than affecting DNA methylation. Moreover, inhibiting glutamate pathway with MK801 could significantly delay tumor growth, with reduced TAMs in implanted Hepa1-6 mouse HCC models. Our work suggested that glutamate could induce CCL2 expression to promote TAM infiltration by negatively regulating EZH2 levels in hepatoma cells, which might serve as a potential prognostic marker and a therapeutic target for HCC patients.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2497172"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12026252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051363","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":"Cross-disease integration of single-cell RNA sequencing data from lung myeloid cells reveals TAM signature in <i>in vitro</i> model.","authors":"Catarina Pinto, Jakub Widawski, Sophie Zahalka, Barbara Thaler, Linda C Schuster, Samuel W Lukowski, Fidel Ramírez, Iñigo Tirapu","doi":"10.1080/2162402X.2025.2502278","DOIUrl":"10.1080/2162402X.2025.2502278","url":null,"abstract":"<p><p>Advancements in single-cell RNA sequencing (scRNA-seq) have revealed the phenotypic and functional diversity of tumor-associated macrophages (TAMs), identifying specific populations that directly impact the antitumor response. However, despite the recognition of TAMs as promising therapeutic targets for cancer treatment, research is hindered by the lack of validated human preclinical models. Here, we applied scRNA-seq to a 3D human cell-based model comprising tumor cell line-derived spheroids, cancer-associated fibroblasts and primary monocytes, a setup widely used in immuno-oncology research. Integration of our <i>in vitro</i> data with publicly available patient-derived datasets showed that the macrophages in this model share phenotypic characteristics with the pro-angiogenic and pro-fibrotic SPP1⁺ TAM population recently found across multiple cancer types and inflammatory lung diseases. This population was linked to aspects of disease progression and associated with poor prognosis in several tumor indications, highlighting the need for relevant models enabling its study as an immunotherapy target. Our research validates the use of a 3D human cell-based culture as a more in vivo-relevant model and enables the preclinical testing of novel macrophage-targeting drugs in a human disease-relevant setup.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2502278"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192378","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":"Characterisation of the tumour microenvironment and PD-L1 granularity reveals the prognostic value of cancer-associated myofibroblasts in non-invasive bladder cancer.","authors":"Carmen G Cañizo, Félix Guerrero-Ramos, Mercedes Perez Escavy, Iris Lodewijk, Cristian Suárez-Cabrera, Lucía Morales, Sandra P Nunes, Ester Munera-Maravilla, Carolina Rubio, Rebeca Sánchez, Marta Rodriguez-Izquierdo, Jaime Martínez de Villarreal, Francisco X Real, Daniel Castellano, Cristina Martín-Arriscado, David Lora Pablos, Alfredo Rodríguez Antolín, Marta Dueñas, Jesús M Paramio, Victor G Martínez","doi":"10.1080/2162402X.2024.2438291","DOIUrl":"10.1080/2162402X.2024.2438291","url":null,"abstract":"<p><p>High-risk non-muscle-invasive bladder cancer (NMIBC) presents high recurrence and progression rates. Despite the use of Bacillus Calmette-Guérin gold-standard immunotherapy and the recent irruption of anti-PD-1/PD-L1 drugs, we are missing a comprehensive understanding of the tumor microenvironment (TME) that may help us find biomarkers associated to treatment outcome. Here, we prospectively analyzed TME composition and PD-L1 expression of tumor and non-tumoral tissue biopsies from 73 NMIBC patients and used scRNA-seq, transcriptomic cohorts and tissue micro-array to validate the prognostic value of cell types of interest. Compared to non-tumoral tissue, NMIBC presented microvascular alterations, increased cancer-associated fibroblast (CAF) and myofibroblast (myoCAF) presence, and varied immune cell distribution, such as increased macrophage infiltration. Heterogeneous PD-L1 expression was observed across subsets, with macrophages showing the highest expression levels, but cancer cells as the primary potential anti-PD-L1 binding targets. Unbiased analysis revealed that myoCAF and M2-like macrophages are specifically enriched in high-grade NMIBC tumors. The topological distribution of these two cell types changed as NMIBC progresses, as shown by immunofluorescence. Only myoCAFs were associated with higher rates of progression and recurrence in three independent cohorts (888 total patients), reaching prediction values comparable to transcriptomic classes, which we further validated using tissue micro-array. Our study provides a roadmap to establish the landscape of the NMIBC TME, highlighting myoCAFs as potential prognostic markers.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2438291"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856324","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":"Plasma protein dynamics during ipilimumab treatment in metastatic melanoma: associations with tumor response, adverse events and survival.","authors":"Ragnhild Reehorst Lereim, Claire Dunn, Elin Aamdal, Sudhir Kumar Chauhan, Oddbjørn Straume, Tormod Kyrre Guren, Jon Amund Kyte","doi":"10.1080/2162402X.2024.2440967","DOIUrl":"https://doi.org/10.1080/2162402X.2024.2440967","url":null,"abstract":"<p><p>The immune checkpoint inhibitor ipilimumab provides long term survival in some metastatic melanoma patients, but the majority has no benefit, and may experience serious side effects. Here, we investigated the dynamics of plasma cytokine concentrations and their potential utility for predicting treatment response, adverse events and overall survival (OS) in patients with metastatic melanoma undergoing ipilimumab monotherapy. A cohort of 148 patients was examined, with plasma samples collected prior to treatment initiation and at the end of the first and second treatment cycles. Concentrations of 48 plasma proteins were measured using a multiplex immunoassay. The results revealed a general increase in cytokine levels following the first ipilimumab dose, consistent with immune activation. Patients not responding to treatment exhibited significantly elevated baseline levels of G-CSF, IL-2RA, MIP-1a, and SCF, compared to tumor responders (<i>p</i> < 0.05). Furthermore, high levels of IL-2RA, IFNγ, PDGF-bb and MIG were linked to inferior OS, while high concentrations of MIF and RANTES were associated with improved OS (<i>p</i> < 0.05). A multivariate model containing CRP, LDH, ECOG, IL-2RA and PDGF-bb identified a subgroup of patients with poor OS. Patients who experienced severe immune-related adverse events within three months of treatment initiation had higher baseline concentrations of several cytokines, indicating a potential association between preexisting inflammation and adverse events. These findings indicate that the first dose of ipilimumab induces a systemic response with increased levels of circulating cytokines and suggest candidate biomarkers for clinical response, immune-mediated toxicity and survival. Further studies in independent patient cohorts are required to confirm the findings.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2440967"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866014","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":"TNFR2/CCR8 bispecific antibody enhances antitumor activity through depleting Ti-Tregs and boosting effector CD8⁺ T cell function.","authors":"Ran Wang, Jiefang Xu, Shipeng Cheng, Zhiyang Ling, Wangmo Sonam, Jichao Yang, Fuquan Jin, Jing Wen, Xiao Lu, Liyan Ma, Yaguang Zhang, Xiaoyu Sun, Chunyan Yi, Bing Sun","doi":"10.1080/2162402X.2025.2497171","DOIUrl":"https://doi.org/10.1080/2162402X.2025.2497171","url":null,"abstract":"<p><p>Modulation or depletion of tumor-infiltrating Tregs (Ti-Tregs) is a promising strategy in the field of antitumor immunotherapy. However, this approach poses challenges due to the diversity within the Treg population and the lack of precision in targeting Ti-Tregs. To selectively and efficiently eliminate Ti-Tregs while sparing other immune cells, we developed a bispecific antibody, FT10-Fab, targeting TNFR2 and CCR8, which are highly expressed on Ti-Tregs. Our results showed that FT10-Fab outperformed the monotherapies in several tumor models by significantly reducing the proportion of Ti-Tregs while increasing the proportion of CD8⁺ T cells. FT10-Fab was able to target and eliminate Ti-Tregs expressing TNFR2 or CCR8 (TNFR2⁺or CCR8⁺ Tregs), particularly TNFR2⁺ CCR8⁺ Tregs, which are the most important proliferative and protumorigenic Tregs. In addition, FT10-Fab relies on CD8⁺ T cells for its antitumor function and induces robust immune memory. Furthermore, the combination of FT10-Fab with PD-1 blockade showed synergistic therapeutic efficacy against tumors by significantly suppressing Tregs and enhancing effector CD8⁺ T cell function. Taken together, our findings suggest that precision depletion of Ti-Tregs via the bispecific TNFR2/CCR8 antibody is a potential therapeutic for cancer immunotherapy, while combination with anti-PD1 amplifies the antitumor effect.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2497171"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988762","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}