Journal for Immunotherapy of Cancer最新文献

{"title":"Poliosis predicts durable response to immune-checkpoint blockade in metastatic melanoma: a multicenter cohort study.","authors":"Annika Brekner, Miriam Mengoni, Julian Kött, Berenice Mareen Lang, Alisa Lepper, Jakob Veeser, Janina Dietzel, Nora Laubach, Andrea Forschner, Christoffer Gebhardt, Stephan Grabbe, Henner Stege, Maximilian Haist","doi":"10.1136/jitc-2026-015306","DOIUrl":"10.1136/jitc-2026-015306","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade (ICB) improved survival outcomes for patients with metastatic melanoma. Yet up to 65% of patients experience primary resistance and nearly half of initial responders acquire resistance. The clinical utility of ICB is further tempered by frequent immune-related adverse events (irAEs), which increase in severity and frequency with prolonged treatment duration. Hence, a pivotal challenge is to identify clinically accessible markers to predict durable ICB responses. While prior reports indicate that the development of cutaneous irAEs may reflect robust antitumor immune responses, there is limited evidence linking specific types of cutaneous irAEs to clinical ICB benefit.</p><p><strong>Methods: </strong>In this retrospective multicenter study, we investigated a cohort of 741 patients diagnosed with non-resectable stage III/IV melanoma who were treated with ICB between April 2012 and August 2025. Patient demographics, tumor characteristics, treatment regimens and survival outcomes were collected within six German skin cancer centers. We stratified patients by the type of cutaneous AE into such with whitening of the body skin (vitiligo), hair (poliosis) or other cutaneous AE. Primary endpoints included progression-free survival (PFS) and objective response rates (ORR).</p><p><strong>Results: </strong>Among 741 eligible patients, 221 developed cutaneous irAE within the median follow-up period of 48 months. Thereof, we observed tumor recurrences in 17.2% of patients with poliosis, 57.7% of patients developing vitiligo and 60.0% of patients with other cutaneous irAE. In line, we detected a significantly enhanced ORR (93.1% vs 58.8% vs 38.8%, p<i><</i>0.001), prolonged PFS (Not reached, NR, vs 31 months vs 9 months, p<i><</i>0.001) and overall survival (NR vs NR vs 69 months, p<0.001) in poliosis patients. Critically, enhanced tumor control in poliosis patients was seen regardless of initial tumor burden, treatment duration or the presence of melanoma brain metastases. While other AE usually arise early on ICB start, poliosis was a late event that occurred at a median of 6 months.</p><p><strong>Conclusions: </strong>Our study identifies poliosis as a distinct and immunologically-informed marker linked to strong and durable ICB responses easily applicable in a routine clinical setting. Detection of poliosis may complement radiographic imaging for clinical decision-making on ICB treatment duration and early cessation and provides a window for translational investigations harnessing epitope-specific T-cell responses to melanoma antigens.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRTN3 drives immunosuppression in KRAS-mutant lung adenocarcinoma through proteolytic inactivation of CXCL9.","authors":"Yi Liu, Chen Zhang, Jia Li, Chong Chen, Song Xu, Tong Li, Huilin Chen, Yigong Hou, Jiayu Jiang, Haojie Chen, Wei Wang, Rong Xiang, Renle Du, Yunping Luo","doi":"10.1136/jitc-2026-015399","DOIUrl":"10.1136/jitc-2026-015399","url":null,"abstract":"<p><strong>Background: </strong>KRAS-mutant lung adenocarcinoma (LUAD) shows limited benefit from immune checkpoint blockade (ICB), and the mechanisms by which oncogenic KRAS signaling promotes immune resistance remain poorly understood. Here, we sought to identify tumor-intrinsic mediators of KRAS-driven immune evasion and therapeutic resistance in LUAD.</p><p><strong>Methods: </strong>Integrated analyses of human LUAD cohorts, genetically engineered mouse models, tumor cell models, and patient-derived organoids were performed to define the role of PRTN3 in immune regulation. PRTN3 regulation and function were investigated using transcriptional analyses, chromatin immunoprecipitation assays, biochemical cleavage assays, and immune cell co-culture systems. The therapeutic effect of PRTN3 inhibition was evaluated using flow cytometric immune profiling, functional immune assays, and syngeneic tumor models.</p><p><strong>Results: </strong>We identified PRTN3 as a downstream effector of KRAS signaling that promotes immune evasion in LUAD. Mechanistically, KRAS signaling transcriptionally upregulated PRTN3 through c-Myc activation. Secreted PRTN3 directly cleaved and inactivated CXCL9 in the tumor microenvironment, disrupting CXCL9/CXCR3 signaling and impairing the recruitment and activation of cytotoxic CD8⁺ T cells and natural killer cells. In patients with LUAD, elevated PRTN3 expression was associated with reduced cytotoxic immune signatures and decreased CXCL9 activity. Genetic inhibition of PRTN3 enhanced antitumor immunity and improved responses to anti-programmed cell death protein 1 therapy in vivo. Furthermore, a hydrolysis-resistant CXCL9 variant restored cytotoxic lymphocyte activation and enhanced immune-mediated tumor cell killing in patient-derived organoids.</p><p><strong>Conclusions: </strong>Our findings reveal a KRAS/c-Myc/PRTN3 axis that promotes immune suppression through extracellular proteolytic inactivation of CXCL9. Targeting PRTN3-mediated immune evasion may represent a promising strategy to enhance ICB efficacy in KRAS-driven LUAD.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Propionate promotes CD8⁺ T-cell infiltration and enhances immunotherapy efficacy in colorectal cancer.","authors":"Jingying Pan, Le Tong, Rushan Fei, Kai Wu, Jia Ji, Ting Sun, Yinuo Zhao, Jun Zhang, Hanhan Feng, Hanju Hua, Hang-Ping Yao","doi":"10.1136/jitc-2026-015279","DOIUrl":"https://doi.org/10.1136/jitc-2026-015279","url":null,"abstract":"<p><strong>Background: </strong>Short-chain fatty acids (SCFAs) produced by the gut microbiota are increasingly recognized as regulators of host immunity, yet the role of individual SCFAs in shaping the tumor immune microenvironment in colorectal cancer (CRC) remains poorly defined. This study aims to investigate the role of propionate in antitumor immunity and immunotherapy responsiveness in CRC.</p><p><strong>Methods: </strong>SCFA levels, systemic inflammatory cytokine levels, and immune cell subsets were quantified in peripheral blood and tumor tissues from patients with CRC and healthy controls. Syngeneic microsatellite instability-high (MSI-H) and microsatellite stable (MSS) murine CRC models were used to evaluate the therapeutic efficacy of propionate alone and in combination with anti-programmed death-ligand 1 (PD-L1) blockade. CD8⁺ T-cell infiltration, activation status, and cytotoxic function were assessed by flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Mechanistic investigations included acetylation-dependent protein modification analyses. Molecular analyses of signaling pathways were performed to delineate the regulatory axis underlying propionate-mediated immune modulation.</p><p><strong>Results: </strong>Propionate levels were inversely associated with systemic inflammation and positively correlated with intratumoral CD8⁺ T-cell infiltration. Propionate supplementation enhanced CD8⁺ T-cell cytotoxicity, promoted CD8⁺ T-cell tumor infiltration and suppressed tumor growth in both MSI-H and MSS mouse models. Notably, propionate significantly potentiated the efficacy of PD-L1 blockade and restored immunotherapy sensitivity in otherwise resistant MSS tumors. Mechanistically, propionate induced acetyl-CoA acetyltransferase 1-dependent acetylation and proteasomal degradation of argininosuccinate synthase 1 (ASS1), resulting in activation of signal transducer and activator of transcription 1 signaling and upregulation of the T cell-recruiting chemokine C-X-C motif chemokine ligand 9. In clinical samples, low ASS1 expression was associated with high CD8⁺ T-cell infiltration.</p><p><strong>Conclusions: </strong>This study revealed the role of propionate in regulating the tumor immune microenvironment in CRC, suggesting propionate as a promising strategy to overcome immune exclusion and enhance the efficacy of immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toripalimab consolidation after chemoradiotherapy in limited-stage small cell lung cancer: a phase II, randomized controlled study (GASTO-1052A).","authors":"Pengxin Zhang, DaQuan Wang, Wenzhuo He, HongMei Zhang, Yumei Dong, Yu Situ, MengRu Wang, Yujiao Zhang, ShiHong Wei, Bo Qiu, Yan Huang, Hui Liu","doi":"10.1136/jitc-2026-016467","DOIUrl":"10.1136/jitc-2026-016467","url":null,"abstract":"<p><strong>Background: </strong>Immune-checkpoint inhibitors (ICIs) plus chemotherapy have demonstrated survival benefits in extensive-stage small cell lung cancer (SCLC). The integration of immunotherapy with concurrent chemoradiotherapy (CCRT) may improve survival outcomes in limited-stage SCLC (LS-SCLC). This phase II randomized controlled study was designed to evaluate the efficacy and safety of toripalimab consolidation versus observation in patients with LS-SCLC after CCRT.</p><p><strong>Methods: </strong>We conducted this phase II, randomized controlled trial in patients with LS-SCLC who had completed CCRT. Eligible patients were randomized 1:1 to either toripalimab consolidation (240 mg every 3 weeks for up to 6 months) or observation. Randomization was stratified according to disease stage (I or II vs III) and the receipt of prophylactic cranial irradiation (PCI) (yes vs no). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate and toxicities.</p><p><strong>Results: </strong>Between June 30, 2020, and May 31, 2024, a total of 98 patients were randomized to receive either toripalimab consolidation (n=49) or observation (n=49) after CCRT. The trial was prematurely terminated on May 31, 2024. Objective responses were observed in 14 of 23 patients (60.9%) in the toripalimab group and in 9 of 24 patients (37.5%) in the observation group. The median PFS was not reached in the toripalimab group, compared with 14.1 months (95% CI 2.8 to 25.4) in the observation group (HR, 0.55; 95% CI 0.31 to 0.96). The median OS was not reached with toripalimab, compared with 30.3 months (95% CI 20.4 to 40.2) with observation (HR, 0.39; 95% CI 0.19 to 0.80). Treatment-related toxicities were generally mild. Adverse events led to discontinuation of study drug in 6 of 48 patients (12.5%) in the toripalimab group. Grade 3 pneumonitis or radiation pneumonitis occurred in two patient (4.2%) in the toripalimab group and one patient (2.0%) in the observation group. No grade 4 or 5 adverse events occurred in either group. Subgroup analyses of PFS and OS favored toripalimab over observation across all predefined subgroups, including age, sex, Eastern Cooperative Oncology Group performance status, smoking status, disease stage, response to CCRT and the receipt of PCI.</p><p><strong>Conclusion: </strong>Consolidative toripalimab showed promising signals of improved PFS and OS with a manageable safety profile in patients with LS-SCLC. These findings warrant confirmation in larger, adequately powered randomized trials.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTPN22 as a novel therapeutic target: a key intracellular checkpoint for NK cell therapy.","authors":"Tung Nguyen Thanh Uong, Meesun Yoon, Nhat Phuoc Nguong Minh Nguyen, Mijeong Lee, Seung Kwon Koh, Jae-Uk Jeong, Yong-Hyub Kim, Duck Cho","doi":"10.1136/jitc-2026-016896","DOIUrl":"https://doi.org/10.1136/jitc-2026-016896","url":null,"abstract":"<p><strong>Background: </strong>PTPN22, a protein tyrosine phosphatase (PTP) family member, has recently emerged as an intracellular regulator in adaptive immune cells. However, its function in natural killer (NK) cells remains unclear despite its high expression in innate immune cells.</p><p><strong>Methods: </strong>We analyzed single-cell RNA-sequencing (scRNA-seq) datasets and The Cancer Genome Atlas (TCGA) to evaluate PTPN22 expression in NK cells and its association with clinical outcomes. We established a CRISPR-mediated PTPN22 knockout platform for NK cell gene editing and evaluated PTPN22 function using both genetic deletion and pharmacological inhibition across multiple NK cell platforms. Cytotoxicity and cytokine production were assessed against hematologic and solid tumor targets, including CD19⁺ and mesothelin-positive (MSLN⁺) cancer cells. PTPN22 knockout (PTPN22^KO) anti-CD19/CAR-NK92 cells were tested in Nalm6 xenograft models.</p><p><strong>Results: </strong>Published scRNA-seq datasets showed that PTPN22 was highly expressed in tumor-infiltrating NK cells. PTPN22^high NK cells exhibited stress and dysfunction signatures within inflammatory and immunosuppressive tumor microenvironments (TME), with elevated PTPN22 expression in TCGA associated with poorer patient survival. Genetic deletion of PTPN22 or pharmacological inhibition enhanced NK-cell cytotoxicity and pro-inflammatory cytokine release and improved the antitumor activity of chimeric antigen receptor (CAR)-NK cells against CD19⁺ and MSLN⁺ targets. PTPN22^KO preserved CAR-NK cell function under cytokine-based TME-like conditions and improved the functional persistence of primary anti-CD19 CAR-NK cells during prolonged tumor exposure. PTPN22^KO NK and CAR-NK cells showed increased or preserved signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduced FAS expression under inflammatory conditions. Notably, PTPN22^KO anti-CD19/CAR-NK92 cells demonstrated superior anti-leukemic activity and significantly prolonged survival compared with non-knockout controls in vivo.</p><p><strong>Conclusions: </strong>These findings identify PTPN22 as a novel intracellular checkpoint that limits NK and CAR-NK cell function. Targeted deletion of PTPN22 represents a promising strategy to enhance the therapeutic efficacy and persistence of both unmodified and CAR-engineered NK cells for cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hormone therapy potentiates chemoimmunotherapy by inducing SUMOylation-mediated immunogenic cell death.","authors":"Jiaqian Li, Mingzhu Liu, Chunping Wei, Yunxuan Zhou, Ning Wen, Jiang Li, Qiyi Zhao","doi":"10.1136/jitc-2025-014506","DOIUrl":"https://doi.org/10.1136/jitc-2025-014506","url":null,"abstract":"<p><strong>Background: </strong>Combining immunotherapy with endocrine therapy and/or chemotherapy promotes prognosis in patients with estrogen receptor-positive/HER2-negative (ER⁺HER2^-) breast cancer; however, the unclear underlying mechanisms limit their widespread application in clinical practice. This study aimed to investigate how ER signaling regulates antitumor immunity and influences responses to chemoimmunotherapy.</p><p><strong>Methods: </strong>We evaluated pathological complete response rates between ER-positive and ER-negative breast cancer patients across internal and external cohorts treated with immunotherapy and neoadjuvant chemotherapy. Mechanistic studies were conducted to explore the crosstalk between ER and immunogenic cell death (ICD) through high mobility group box 1 (HMGB1) SUMOylation. The therapeutic potential of chemoimmunotherapy regimens was assessed using immunocompetent mouse models of ER⁺ breast cancer.</p><p><strong>Results: </strong>Patients with ER^- breast cancer had higher pathological complete response rates after immunotherapy and neoadjuvant chemotherapy compared with those with ER⁺ breast cancer in both internal and external cohorts. Enhanced immune responses were observed in ER^- breast cancer after chemotherapy, which was attributed to the induction of ICD via the release of HMGB1. Mechanistically, ER inhibits HMGB1 release by directly interacting with the HMG Box B domain and suppressing its SUMOylation at the K114 site, thereby suppressing the antitumor immune response.</p><p><strong>Conclusions: </strong>Therapeutically, combining ER antagonist with chemotherapy potentiated the efficacy of PD-1 blockade through HMGB1 in an immunocompetent mice model. These findings provide new mechanistic insights and clinical strategies for addressing immunotherapy resistance in ER⁺ breast cancer patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening of known gut microbiome-derived metabolites in anti-tumor immunity of colorectal cancer.","authors":"Xinan Zhang, Zixuan Li, Hui Hua, Hao Song, Sangni Qian, Xin Huang, Guiqin Ye, Yingyu Huang, Qin Wang, Boan Zheng, Xiaodong Xu, Yiran Li, Yanli Zhu, Liping Yu, Yeting Hong, Hang Yuan, Jianbin Zhang","doi":"10.1136/jitc-2026-015554","DOIUrl":"10.1136/jitc-2026-015554","url":null,"abstract":"<p><strong>Background: </strong>Most colorectal cancers (CRCs) patients with microsatellite stability (MSS) have minimal benefit from immune checkpoint inhibitor monotherapy, and even after PD-1/PD-L1 blockade, T cell function remains inadequately restored, highlighting the importance of PD-1 downstream signaling events. SHP-2 is a critical effector of PD-1 downstream signaling and plays a key role in establishing the immunosuppressive tumor microenvironment in CRC. Gut microbial metabolites are emerging as regulators of anti-tumor immunity, but their role in modulating the PD-1/SHP-2 interaction remains unknown.</p><p><strong>Methods: </strong>We established a split-luciferase complementation screening system based on the PD-1/SHP-2 interaction and systematically screened a library of human gut microbial metabolites (n=480). The effect of candidate metabolites on T cell function was assessed <i>in vitro</i> using flow cytometry, confocal microscopy, and cell viability assays. Using a mouse colon cancer model, we further investigated the role of taurocholic acid (TCA) and glycodeoxycholic acid (GDCA) in the tumorigenesis and immunotherapy of CRC. Finally, the clinical relevance of metabolite-producing bacterium was examined in tumor specimens from CRC patients (n=53) using fluorescence <i>in situ</i> hybridization and real-time PCR assays.</p><p><strong>Results: </strong>We identified the conjugated bile acids TCA and GDCA as enhancers of the PD-1/SHP-2 interaction. Mechanistically, TCA and GDCA stabilized the PD-1/SHP-2 complex through an allosteric mechanism by promoting PD-1 phosphorylation. Functionally, two metabolites suppressed CD8⁺ T cell activation, proliferation, and cytotoxicity in a PD-1/SHP-2-dependent manner, thereby accelerating tumor progression <i>in vivo</i>. Conversely, pharmacological depletion of TCA and GDCA using the bile acid sequestrant cholestyramine (CHO) effectively reversed their immunosuppressive effect and synergized with anti-PD-1 antibody therapy to inhibit the tumorigenesis of CRC. Clinical sample analysis revealed that the abundance of <i>Clostridium scindens</i>, the primary bacterial source of TCA and GDCA, was inversely correlated with CD8⁺ T cell infiltration in tumor tissues from CRC patients.</p><p><strong>Conclusions: </strong>This study reveals a \"Bile acid-associated metabolites-Immune checkpoint\" regulatory axis that drives immunosuppression in CRC. The identification of TCA and GDCA as endogenous enhancers of PD-1 signaling provides a mechanistic rationale for targeting these metabolites to overcome immunotherapy resistance.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of neuropeptide-mediated immune sensing in the modulation of antitumor immunity.","authors":"Janaina da Silva Vieira, Benedetta Fiordi, Alzbeta Synackova, Christoph Scheiermann, Camilla Jandus","doi":"10.1136/jitc-2026-015967","DOIUrl":"10.1136/jitc-2026-015967","url":null,"abstract":"<p><p>The hallmarks of cancer, first introduced by Hanahan and Weinberg in 2000 and updated in 2011 and in 2022, summarize the core processes that drive the stepwise development of tumors. This framework has proven highly effective for interpreting the vast complexity of cancer and its underlying biology. However, advances in spatially resolved single-cell technologies and more advanced imaging approaches have revealed additional layers of regulation that shape tumor behavior, particularly involving interactions between tumors and the nervous system. Although the influence of innervation on tumor cells and tumor vasculature has been widely studied, the impact of neurotransmitters, neural-derived factors, or neuropeptides on tumor-infiltrating immune cells remains largely unexplored and unexploited. Importantly, immune cells within the tumor microenvironment express receptors for various neural-derived signals, and can shift their phenotypes and adapt their functions in response to these inputs. Here, we highlight neuropeptide-driven pathways that modulate tumor-infiltrating immune cells to influence hallmark functions and, ultimately, shape tumor progression. Neural regulation of the tumor microenvironment is therefore emerging as a promising and potentially targetable layer that could complement existing cancer therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8⁺ T cells while restraining regulatory T-cell accumulation.","authors":"Kathryn M LaPorte, Janika Põder, Daria Ivanova, Molly Dalzell, Paolo Serafini, Alejandro V Villarino, Thomas R Malek","doi":"10.1136/jitc-2026-015104","DOIUrl":"10.1136/jitc-2026-015104","url":null,"abstract":"<p><strong>Background: </strong>Targeting the high-affinity interleukin-2 receptor (IL-2R) on CD8⁺ T effector cells elicits potent antitumor responses that are augmented when co-administered with programmed cell death protein 1 (PD-1) blockade.</p><p><strong>Methods: </strong>Using the mouse IL-2/CD25 fusion protein (mIL-2/CD25) at a high dose (HD) and anti-PD-1 checkpoint blockade, with the CT26 and MC38 colon carcinomas as models, the current study investigated how antitumor responses occurred when regulatory T cells (Tregs) are also a target of HD mIL-2/CD25. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) repertoire analysis of tumor-associated immune cells were used to identify how combination therapy reshaped the tumor microenvironment (TME). These data were cross-referenced with published datasets to (1) corroborate TCR specificity and (2) identify how CD8⁺ T-cell differentiation is affected by different IL-2/PD-1 strategies.</p><p><strong>Results: </strong>Here, we show that effective antitumor immunity by the combination therapy is a result of HD mIL-2/CD25-dependent reprogramming of CD8⁺ tumor-specific T cells that increases their function and supports their expansion within the TME, the latter also shaped by PD-1 blockade. This therapy supports antitumor responses by chemokines and inflammatory cytokines that selectively favor the migration of CD8⁺ T cells but not Tregs deep within the tumor. After HD mIL-2/CD25 treatment, Tregs within the TME showed impaired downstream IL-2R signaling, reflected by failed upregulation of forkhead box P3 and CD25, impaired development into effector Tregs, and enhanced cell death, the latter which likely offsets Treg proliferation. Many similarities were noted after direct comparison of these scRNA-seq findings with another study where IL-2 activity was targeted to PD-1⁺ CD8⁺ T cells. Notably, HD mIL-2/CD25 and anti-PD-1 combination promotes effector and 'stem-like' CD8⁺ T-cell subsets, perhaps even to a greater extent than the PD-1-targeted IL-2 strategy.</p><p><strong>Conclusions: </strong>The efficient differentiation of exhausted CD8⁺ T cells into highly functional cells and the resulting potent antitumor responses by HD mIL-2/CD25 plus anti-PD-1 suggest that this approach may augment durable response rates more than currently achieved with checkpoint blockade monotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In situ APMV-4 vaccination primes systemic response to subtherapeutic dosing of aCTLA-4 in colorectal carcinoma.","authors":"Yonina Bykov, Natalia Alonso Moreda, Naseem Sadek, Gloria Dawodu, Srivatsan Swaminathan, Stephen T Yeung, Daniel Lozano Ojalvo, Javier De Las Rivas, Jeffrey A Tomalka, Adolfo García-Sastre, Sara Cuadrado-Castano","doi":"10.1136/jitc-2026-015859","DOIUrl":"10.1136/jitc-2026-015859","url":null,"abstract":"<p><strong>Background: </strong>Colorectal carcinoma (CRC) is frequently typified by chronic inflammation and high levels of immunosuppression that render it resistant to immunotherapy. The multimodal immunostimulatory mechanisms of oncolytic virotherapy make it an attractive strategy for priming tumors for immune-checkpoint blockade (ICB). Here, we present an emerging oncolytic virotherapeutic, rAPMV-4, with previously described efficacy in preclinical models of CRC and melanoma.</p><p><strong>Methods: </strong>We expand on the established efficacy of APMV-4 by characterizing responses to the virotherapy in preclinical single and bilateral MicroSatellite Stable CRC tumor models. To investigate local and systemic effects of the virus, we characterized responses in tumors, draining lymph nodes, and sera using RNA-seq, high-dimensional flow cytometry, and cytokine analysis.</p><p><strong>Results: </strong>rAPMV-4 induced rapid, yet transient, interferon signaling, and early signatures of antigen presentation and T cell activation. Comparison with a human CRC cohort revealed a transcriptomic shift induced by the virus from a mesenchymal CMS4 to an \"immune-high\" CMS1 subtype predicted to respond well to ICB. Leveraging these signatures of response and resistance to the virotherapy, we designed a rational combinatorial approach with low-dose anti-CTLA-4, which reversed Treg activation and alleviated CD4 and CD8 dysfunction, leading to more potent systemic tumor elimination.</p><p><strong>Conclusions: </strong>This work supports the further clinical development of rAPMV-4, either alone or in combination, as an efficacious therapy for CRC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}