Journal for Immunotherapy of Cancer最新文献

{"title":"TCASIA: an integrative atlas linking alternative splicing landscapes for cancer immunotherapy.","authors":"Yihao Zhang, Yunzhi Guo, Haitao Wang, Yi Xiong, Minjun Chen, Ying Cai, Xin Li, Jun Wu, Jiaqi Hao, Su-Han Jin, Wei Zhang, Luohuan Dai, Hongwei Liu, Jianfeng Li, Jiahui Zhang, Markus Hecht, Benjamin Frey, Udo S Gaipl, Xin Chen, Xuejun Li, Shixiang Wang, Hu Ma, Jian-Guo Zhou","doi":"10.1136/jitc-2026-015364","DOIUrl":"10.1136/jitc-2026-015364","url":null,"abstract":"<p><strong>Background: </strong>Identifying robust predictive biomarkers for immune checkpoint blockade (ICB) remains a challenge. While alternative splicing (AS) shapes tumor immunity, the lack of large-scale, consensus-based datasets constrains the characterization of ICB-specific splicing landscapes.</p><p><strong>Methods: </strong>We developed TCASIA (the Cancer Alternative Splicing Immunotherapy Atlas), harmonizing >4000 samples across 29 cohorts. A rigorous \"2-out-of-4\" multi-algorithm consensus framework (rMATS, MAJIQ, SUPPA2, and SplAdder) with a fuzzy matching strategy was used to establish a high-confidence AS landscape.</p><p><strong>Results: </strong>TCASIA provides a robust toolkit linking splicing perturbations with clinical phenotypes (response, survival, and immune infiltration). Using this platform, we recapitulated the established <i>FAS</i> exon 6 skipping mechanism and identified <i>IL7R</i> exon 6 skipping as a functionally supported candidate associated with reduced CD8⁺ T-cell infiltration and poor survival in melanoma.</p><p><strong>Conclusions: </strong>TCASIA provides an analytical atlas for investigating splicing-mediated immune evasion and prioritizing isoform-specific candidates for further functional and clinical validation in the context of ICB treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127502","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":"Impact of adjuvant therapy on melanoma-specific survival in elderly patients with high-risk resected melanoma: a multicenter international retrospective study.","authors":"Andrea Boutros, Janet McKeown, Roger Olofsson Bagge, Lars Ny, Jan Mattsson, Francesco Spagnolo, Enrica Teresa Tanda, Ralf Gutzmer, Piyush Grover, Lydia Warburton, Muhammad Adnan Khattak, Douglas B Johnson, Kyle P Maas, Hannah Burnette, Ryan J Sullivan, Derek Effiom, Aleigha R Lawless, Paolo A Ascierto, Vito Vanella, Caroline Gaudy-Marqueste, Nausicaa Malissen, Tobias Peres, Anadil Javaid, Praveena Idaikkadar, Celeste Lebbé, Laetitia Da Meda, Hazel Burke, Ines Pires da Silva, Alexander C J van Akkooi, Matteo S Carlino, Serigne N Lo, Georgina V Long, Alexander M Menzies","doi":"10.1136/jitc-2026-016060","DOIUrl":"10.1136/jitc-2026-016060","url":null,"abstract":"<p><strong>Purpose: </strong>Adjuvant systemic therapy improves recurrence-free survival in resected high-risk melanoma, but elderly patients remain markedly under-represented in clinical trials; their competing risk of death from other causes needs to be considered. Consequently, the clinical benefit of adjuvant therapy in older populations remains uncertain. We conducted an international real-world study to evaluate survival outcomes of patients aged ≥75 years with resected stage III-IV melanoma managed with adjuvant systemic therapy or observation.</p><p><strong>Methods: </strong>In this multicenter retrospective cohort study, patients aged ≥75 years with completely resected stage III-IV cutaneous melanoma were identified across 14 international melanoma centers. Patients received either standard adjuvant systemic therapy (anti-programmed cell death protein 1 immunotherapy or BRAF/MEK-targeted therapy) or observation. The primary endpoint were melanoma-specific survival (MSS) and overall survival (OS). Secondary endpoints included recurrence-free survival (RFS). Survival outcomes were estimated using Kaplan-Meier methods and evaluated with multivariable Cox regression models adjusted for age, stage, sex, and mutation status.</p><p><strong>Results: </strong>A total of 580 patients were included (median age 79 years; range, 75-99), of whom 222 (38%) received adjuvant therapy and 358 (62%) underwent observation. Adjuvant therapy was associated with significantly improved MSS, with 5-year MSS of 74% compared with 60% in the observation group (adjusted HR 0.58; 95% CI 0.40 to 0.85; p=0.005), as well as OS (adjusted HR 0.66, 95% CI 0.51 to 0.87; p=0.002). Adjuvant therapy was also associated with improved RFS (HR 0.57, 95% CI 0.45 to 0.72; p<0.0001). Among patients managed with observation, disease recurrence occurred in 69%, yet only 47% of those patients received systemic therapy as first-line management of recurrence. Notably, among observation patients who remained recurrence-free or received systemic therapy after recurrence, MSS was comparable to that observed in adjuvant-treated patients (HR 0.83; 95% CI 0.55 to 1.25).</p><p><strong>Conclusion: </strong>In this large international real-world cohort of elderly patients with resected melanoma, adjuvant therapy was associated with clinically meaningful improvements in MSS, OS and RFS. Although immunotherapy retained efficacy when administered at recurrence, many elderly patients did not receive systemic therapy as first-line management of recurrence. Adjuvant therapy may therefore represent an important strategy to ensure timely access to effective treatment in carefully selected older patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136828","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":"PARP1-selective inhibitor DSB1559 demonstrates superior efficacy and antitumor immunity in triple-negative breast cancer.","authors":"Adam Nelson, Kelly F Zheng, Carlos Wagner S Wanderley, Daniel E Michaud, Phillip M Cowley, Gillian M Campbell, Bose Kochupurakkal, Yuqing Jiao, Carman Man-Chung Li, Filipa Lynce, Geoffrey I Shapiro, Barry E McGuinness, Alan Wise, Jennifer L Guerriero","doi":"10.1136/jitc-2025-014578","DOIUrl":"10.1136/jitc-2025-014578","url":null,"abstract":"<p><strong>Background: </strong>Poly (ADP-ribose) polymerase inhibitors (PARPis) have improved outcomes of BRCA-associated breast cancer; however, treatment-related toxicity remains a major clinical challenge. Currently approved PARPis broadly inhibit multiple members of the PARP protein family. However, preclinical studies suggest that inhibition of PARP1 alone is sufficient to drive antitumor efficacy. In contrast, inhibition of PARP2 has been implicated in hematological toxicities seen in patients receiving PARPi therapy. Therefore, selectively inhibiting PARP1 may reduce toxicity for patients. Here, we characterize and test the PARP1-selective inhibitor DSB1559 in preclinical models of Brca1-associated triple-negative breast cancer (TNBC).</p><p><strong>Methods: </strong>Pharmacokinetic/pharmacodynamic assays were performed to examine DSB1559 potency, selectivity, and in vivo behavior. Immunocompetent FVB/n mice bearing Brca1-deficient TNBC (CMV-Cre;Brca1^fl/fl;Trp53^fl/fl) tumors were treated with olaparib or DSB1559 and followed for survival. Flow cytometry and bulk RNA-sequencing were performed to measure the effects on the tumor microenvironment (TME).</p><p><strong>Results: </strong>DSB1559 had superior selectivity for PARP1 and increased overall survival compared with olaparib. Analysis of the TME revealed a significant increase in cytotoxic T-cells, activated dendritic cells, and genes associated with antitumor immunity in mice treated with DSB1559.</p><p><strong>Conclusions: </strong>Taken together, DSB1559 is a highly selective PARP1 inhibitor that demonstrates superior efficacy and antitumor immune response compared with olaparib. A structurally related, clinical lead compound (DSB2455) is now being tested in a phase Ia/Ib clinical trial (NCT06458712).</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127411","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":"Targeting CD6 in solid tumors: safety, early efficacy, and mechanistic insights from a proof-of-concept trial of itolizumab.","authors":"Cynthia González Muñoz, Raiza Ruiz-Lorente, Olivia Blanco-Pita, Noralys Lara-Fernández, Eva Elena Salomón, Alexis Alvárez Lobaina, Jenysbel de la Caridad Hernandez Reyes, Patricia Lorenzo-Luaces Álvarez, Mayelín Troche-Concepción, Loipa Medel Perez, Yanela Santiesteban-González, Daymys Estevez-Iglesias, Arasay Montes-D'Santis, Aymé Fernández-Calienes Valdés, Tania Crombet Ramos, Mayra Ramos Suzarte, Mayrel Labrada Mon","doi":"10.1136/jitc-2026-016182","DOIUrl":"10.1136/jitc-2026-016182","url":null,"abstract":"<p><strong>Background: </strong>CD6 is a promising target in cancer immunotherapy, with preclinical evidence supporting its role in modulating immune responses. This warrants further investigation into current CD6-targeting treatments, which could lead to new anti-tumor therapies. However, the clinical effects of targeting CD6 in solid tumors remain unexplored.</p><p><strong>Methods: </strong>This proof-of-concept study is the first in-human evaluation of the safety and early effectiveness of anti-CD6 monoclonal antibody itolizumab in patients with advanced, highly heterogeneous solid tumors. Treatment had two phases: induction and maintenance. In induction, group A received 100 mg weekly for nine doses; group B received 200 mg biweekly for five doses. After completing induction, patients moved to maintenance 21 days later, receiving 100 mg every 21 days for up to six doses. The primary endpoint was safety; secondary objectives included disease control, survival, and exploratory molecular mechanisms and blood biomarkers.</p><p><strong>Results: </strong>Itolizumab demonstrated a favorable safety profile, with no safety-related treatment discontinuations, no related serious adverse events, and no unexpected toxicities. In this heavily treated, non-biomarker-selected population, disease control was achieved in 25% in group A and 20% in group B, and the 1-year survival rate was 26% in group A and 15% in group B. Mechanistically, ex vivo analysis demonstrated that itolizumab downregulates CD6, increasing soluble CD6 levels and promoting a cytotoxic phenotype on CD8 and NK cells. Additionally, patient-derived peripheral blood mononuclear cells demonstrated boosted in vitro killing capacity specifically against CD318+ cancer cells. The antibody also modulates PD-1 expression in peripheral lymphocytes, promoting NK cell activity while maintaining inhibitory signals on CD8+ T cells and decreasing T helper overactivation. These findings support the dual role of itolizumab, enhancing anti-tumor responses while preventing autoimmune-like effects by reducing off-target inflammation and avoiding immune-related adverse effects associated with immune checkpoint therapies.</p><p><strong>Conclusions: </strong>Overall, these findings support further development of itolizumab as a rational immunomodulatory strategy with a favorable safety profile for advanced solid tumors, particularly in CD318-expressing tumors and as part of rational combination regimens.</p><p><strong>Trial registration number: </strong>RPCEC00000444.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127427","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":"IL7R mRNA therapy enhances antitumor T cell immunity and suppresses tumor growth in preclinical tumor models.","authors":"Adeel Ur Rehman, Muhammad Naveed Khan, Aleena Akhtar, Qianshan Qin, Xiaojing Zhang, Muhammad Arif Asghar, Dandan Ling, Pei Wang, Ying Luo, Zhihuai Wang, Lexin Wang, Hanyang Liu, Xiaosong Li","doi":"10.1136/jitc-2026-017160","DOIUrl":"10.1136/jitc-2026-017160","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-7 receptor (IL7R) signaling is critical for T-cell survival, homeostasis, and immune function, but the therapeutic potential of increasing IL7R expression through messenger RNA (mRNA) delivery remains poorly defined. We investigated whether IL7R mRNA therapy could enhance antitumor immunity and improve tumor control in preclinical cancer models.</p><p><strong>Methods: </strong>IL7R mRNA formulated in lipid nanoparticles (LNPs) was administered by combined intratumoral and intravenous injection in syngeneic B16 melanoma and Lewis lung carcinoma (LLC) models, with empty LNPs included as vehicle controls. Therapeutic efficacy, IL7R expression, immune responses, transcriptomic remodeling, T-cell receptor (TCR) repertoire changes, and treatment tolerability were evaluated using complementary molecular, immunological, and sequencing approaches.</p><p><strong>Results: </strong>IL7R mRNA treatment increased IL7R transcript and protein levels in tumor-bearing mice, whereas empty LNPs did not produce comparable increases. Treatment increased tumor-infiltrating CD8 T-cell frequencies, suppressed tumor growth and prolonged survival in both B16 and LLC models; empty LNP controls did not reproduce the therapeutic effect. Cytokine and transcriptomic analyses showed treatment-associated activation of inflammatory, T-cell, interferon, and antigen-receptor signaling programs. TCR sequencing further demonstrated increased repertoire diversity and reduced clonal dominance following IL7R mRNA treatment. No obvious body-weight loss or marked changes in serum alanine aminotransferase, aspartate aminotransferase, or creatinine were observed under the tested conditions.</p><p><strong>Conclusions: </strong>IL7R mRNA therapy increases IL7R expression and is associated with enhanced T-cell antitumor responses, tumor growth suppression, improved survival, and remodeling of the tumor immune environment. These findings support further mechanistic and preclinical evaluation of IL7R mRNA-based cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 10","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127384","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":"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}