Journal for Immunotherapy of Cancer最新文献

{"title":"Rapid response: Context-dependent immunomodulatory effects of JAK inhibition in the management of severe immune-related adverse events.","authors":"Lingrong Tang, Wenbin Mo, Nan Li, Guangwei Tian","doi":"10.1136/jitc-2025-014677","DOIUrl":"https://doi.org/10.1136/jitc-2025-014677","url":null,"abstract":"<p><p>Recent studies have indicated that Janus kinase inhibitors (JAKi) exert context-dependent immunomodulatory effects in cancer immunotherapy. In this rapid response, we comment on the prospective cohort study by Habib <i>et al</i>, which evaluates JAKi for steroid-refractory or life-threatening immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). The study demonstrated a clinical remission rate of 70.8%, with notable activity in myocarditis and inflammatory arthritis. Although JAK inhibition has historically raised concern due to the central role of JAK-signal transducer and activator of transcription (STAT) signaling in interferon-mediated antitumor immunity, emerging clinical data indicate more nuanced effects influenced by timing, dosing, and immune context. This framework may help explain the observed efficacy of JAKi in controlling severe irAEs without an apparent excess of opportunistic infections. We also emphasize unresolved safety considerations, including thromboembolic risk and disease progression during follow-up. Given the clinical heterogeneity of the cohort and the limited oncologic detail, further prospective studies with stratified and time-to-event analyses are needed to better define the role of JAK inhibition in balancing irAE control and antitumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771547","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":"ILC2s and their immune checkpoints in the antitumor response.","authors":"Cecilia Ciancaglini, Silvia Santopolo, Paola Vacca, Lorenzo Moretta, Linda Quatrini","doi":"10.1136/jitc-2025-014183","DOIUrl":"https://doi.org/10.1136/jitc-2025-014183","url":null,"abstract":"<p><p>Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that patrol mucosal barriers. Among ILC subsets, ILC2s' involvement in the innate immune response to parasites, in the development of asthma and in the repair of damaged tissues is well known. However, their role in antitumor immune response is controversial, as it seems to be dependent on the type of cancer and on interaction with the other cell types in the microenvironment. Immune checkpoint expression and function have been studied recently in ILC2s, with a focus on programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4). This review summarizes recent progress in understanding the ILC2s' contribution to cancer development and response to immunotherapy targeting inhibitory checkpoints.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147772112","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":"Phase 2 trial of pTVG-HP ± pTVG-AR DNA vaccines and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC).","authors":"Christos E Kyriakopoulos, Russell K Pachynski, Jens C Eickhoff, Tommaso P Tonelli, Donghwan Jeon, Douglas G McNeel","doi":"10.1136/jitc-2025-014323","DOIUrl":"https://doi.org/10.1136/jitc-2025-014323","url":null,"abstract":"<p><strong>Background: </strong>We previously reported a trial using pembrolizumab with a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Favorable clinical outcomes were associated with T-cell activation, suggesting immune response to vaccination was critical. In the current trial, we evaluated whether immunization with two vaccines, to broaden the T-cell response to other cancer-associated antigens, would elicit greater anti-tumor efficacy.</p><p><strong>Materials and methods: </strong>60 patients with mCRPC were treated with vaccine on days 1 and 8 of a 3 week cycle, with pembrolizumab given on day 1 of each cycle. Patients in Arm A (n=30) received pTVG-HP as the vaccine, and patients in Arm B (n=30) received pTVG-AR (encoding the ligand-binding domain of the androgen receptor) alternating with pTVG-HP every two cycles. After eight cycles (6 months), patients continued to receive pembrolizumab alone, with the option to receive further booster immunizations at prostate-specific antigen (PSA) progression. The primary objective was 6-month progression-free survival (PFS). Secondary objectives included safety, objective response rate, PSA response rate, overall survival (OS), and immunological evaluations.</p><p><strong>Results: </strong>Overall median time to progression was 24 weeks (24 weeks Arm A, 24 weeks Arm B, p=0.80). The month 6 PFS rate was 51% in Arm A and 45% in Arm B. Median OS was 2.8 years (2.5 years Arm A, 3.7 years Arm B, p=0.16). 20% of patients in each arm experienced a PSA decline of >50%. 20 patients (n=8 Arm A, n=12 Arm B) had measurable disease, and 6/20 (30%) experienced a partial response. Eight patients received booster immunizations after 6 months, 3 of whom subsequently experienced a PSA decline. Three patients in Arm B experienced creatine kinase elevation with or without increased transaminases, which were not observed in Arm A. T cell immune responses to both antigens were detected in patients treated in Arm B.</p><p><strong>Conclusions: </strong>Treatment with DNA vaccines and pembrolizumab demonstrated anti-tumor activity in terms of PSA declines and objective responses. The addition of pTVG-AR did not significantly increase measures of clinical efficacy; however, it was associated with a slight increase in toxicity to tissues that also express AR.</p><p><strong>Trial registration number: </strong>NCT04090528.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771473","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":"Single-cell dissection of persistent tumor antigens in non-responders reveals opportunities for TAA-targeted vaccination after neoadjuvant therapy in esophageal squamous cell carcinoma.","authors":"Ruixiang Zhang, Shu Qi, Yang Zhou, Ying Hu, Yang Li, Yue Li, Jianjun Qin, Ai-Rong Yang, Henghui Zhang, Zhihua Liu, Yin Li","doi":"10.1136/jitc-2025-014562","DOIUrl":"https://doi.org/10.1136/jitc-2025-014562","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant immune checkpoint blockade (ICB) combined with chemotherapy has demonstrated higher response rates than chemotherapy alone in resectable esophageal squamous cell carcinoma (ESCC). Although tumor microenvironment (TME) features associated with treatment response have been studied in the contexts of both chemotherapy and immunotherapy, direct comparisons of these characteristics and their implications for novel therapeutic development remain largely unexplored.</p><p><strong>Methods: </strong>Paired pretreatment and post-treatment tumor samples were prospectively collected from 55 patients with locally advanced ESCC enrolled in a multicenter, phase 3 clinical trial (ChiCTR2000040034). Patients were randomized to receive neoadjuvant chemotherapy (paclitaxel with cisplatin, TP; n=14) or its combination with PD-1 blockade (camrelizumab, albumin-bound paclitaxel and cisplatin/paclitaxel and cisplatin, Cam+nab-TP/TP; n=41), followed by surgical resection. Pathological response was defined based on Mandard's Tumor Regression Grade scoring system. Changes in immune cell populations and tumor-associated antigens (TAAs) within the TME in relation to response were characterized using single-cell RNA and T cell receptor sequencing.</p><p><strong>Results: </strong>Both chemotherapy and chemoimmunotherapy responders exhibited shared temporal dynamics including dendritic cell remodeling, cytotoxic CD8⁺ T cell contraction, and memory T cell expansion, with chemoimmunotherapy uniquely suppressing the clonal expansion of GZMB⁺TIGIT⁺ T cells. In contrast, non-responders failed to elicit effective antitumor immunity and displayed persistent expression of targetable TAAs, fully preserved HLA machinery, and clonal expansion of dysfunctional GZMB⁺TIGIT⁺ T cells.</p><p><strong>Conclusions: </strong>Our study identifies key immune contributors correlated with response to neoadjuvant therapies and a panel of TAAs in non-responders. These findings support the development of TAA-targeted therapeutic vaccines and combination strategies incorporating ICB to overcome resistance in non-responders.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771801","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":"Time-of-day of first checkpoint inhibitor dose influences clinical outcomes and immune responses in hepatocellular carcinoma.","authors":"Howard L Li, Soren Charmsaz, Benjamin J Reisman, Franshisca Hayek, Madelena Brancati, James M Leatherman, Carlotta Pazzi, Royce P Lee, Xiyu Zhao, Eric Christenson, Waqar Arif, Jeric Hernandez, Caroline Ellis, Nicole E Gross, Chris Thoburn, G Scott Chandler, Rajat Mohindra, Sanjay Bansal, Laura Tang, Aditi Guha, Chi V Dang, Neeha Zaidi, Elizabeth M Jaffee, Daniel Laheru, Daniel J Zabransky, Marina Barretti, Won Jin Ho, Mark Yarchoan, Mari Nakazawa","doi":"10.1136/jitc-2025-014070","DOIUrl":"10.1136/jitc-2025-014070","url":null,"abstract":"<p><strong>Background: </strong>Although immune checkpoint inhibitors (ICIs) have long half-lives, preclinical and retrospective clinical studies across multiple tumor types suggest that the time-of-day of ICI infusion may influence therapeutic efficacy by aligning initial drug exposure with circadian peaks in T-cell responsiveness. The immunological basis of this phenomenon and its clinical relevance in hepatocellular carcinoma (HCC) remains unknown.</p><p><strong>Methods: </strong>We followed patients with advanced HCC receiving ICI therapy at Johns Hopkins from 2021 to 2025, classifying them into a morning (first treatment before 12:00 hours) or afternoon (first treatment after 12:00 hours) group. We assessed clinical outcomes and compared immunological responses from baseline to early-on-treatment by profiling peripheral blood mononuclear cells using cytometry by time-of-flight and plasma cytokines using a 39-plex Luminex assay.</p><p><strong>Results: </strong>Our cohort included 84 patients, 39 of whom received their first infusion in the morning. There were no statistically significant differences in baseline demographic or clinical characteristics between patients initiating therapy in the morning versus afternoon. The morning group had superior progression-free survival (multivariable HR 0.50, 95% CI 0.30 to 0.84, p<0.01) and higher odds of treatment response (multivariable OR 3.26, 95% CI 1.08 to 10.90, p<0.05), with no significant increase in immune-related adverse events. The timing of subsequent infusions after the first dose had no impact on outcomes. Immunological responses diverged after the initial dose, with morning-treated patients showing reduced interleukin (IL)-6 levels (p<0.01) and greater expansion of cytotoxic central memory CD8+ T cells (p=0.01) as well as cytotoxic effector and effector memory CD8+ T cells (p=0.06).</p><p><strong>Conclusions: </strong>Morning first-dose infusion of ICIs in HCC was associated with improved clinical outcomes and distinct immune responses, including reduced IL-6 signaling and expansion of cytotoxic central memory CD8+ T cells. These findings suggest that the timing of the initial infusion can imprint an immunological program that shapes subsequent antitumor immunity, providing a mechanistic rationale for strategically scheduling ICI administration.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771820","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":"Novel NK cell-like phenotype expressing CCR5 and its ligands elicits tumor-specific acquired immunity to carcinomatous peritonitis via host NK-derived IFN-γ.","authors":"Situo Zheng, Yui Harada, Yosuke Morodomi, Noriko Yasuda, Kenta Ishimoto, Yoshikazu Yonemitsu","doi":"10.1136/jitc-2025-014300","DOIUrl":"10.1136/jitc-2025-014300","url":null,"abstract":"<p><strong>Background: </strong>Natural killer (NK) cell-based immunotherapies remain largely ineffective against solid tumors and strategies that directly enhance NK cell cytotoxicity often fail to establish durable tumor control. To address this limitation, we developed GAIA-102, a novel NK-like phenotype with enhanced tumor-homing capacity, and its scalable derivative, expanded GAIA-102 (exp_GAIA). Here, we evaluated whether exp_GAIA can engage host immunity to drive durable response.</p><p><strong>Methods: </strong>A syngeneic lethal murine model of carcinomatous peritonitis was used to assess exp_GAIA. Following adoptive transfer of exp_GAIA with recombinant human interleukin-2 (rhIL-2), antitumor efficacy, survival and immune response were evaluated. Mechanistic studies quantified chemokine production and examined CCR5-dependent recruitment and expansion of endogenous NK cells, interferon-γ (IFN-γ) secretion, and activation of tumor-specific CD8⁺T cells. Tumor immunogenic cell death (ICD) was assessed by calreticulin (CRT) surface translocation and analyzed for its association with endogenous NK expansion.</p><p><strong>Results: </strong>Treatment with exp_GAIA plus rhIL-2 induced complete tumor regression and generated durable, tumor-specific adaptive immune response that required CD8⁺T cells. Mechanistically, exp_GAIA secreted CCR5-binding chemokines, particularly CCL3, thereby recruiting endogenous NK cells into tumor. Endogenous NK cells produced IFN-γ, which activated tumor-specific CD8⁺T cells and established an innate-to-adaptive cytotoxicity axis. In parallel, exp_GAIA triggered tumor ICD characterized by CRT translocation, which further promoted in situ expansion of endogenous NK cells.</p><p><strong>Conclusions: </strong>In combination with rhIL-2, exp_GAIA integrates endogenous NK activity with induction of long-lasting, CD8⁺T cell-dependent antitumor immunity via a CCR5-CCL3-NK-IFN-γ-CD8 pathway, reinforced ICD with CRT exposure. These findings support exp_GAIA+rhIL-2 as a new NK-based strategy for durable control of solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728983","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":"Single-cell and spatial transcriptomics reveal that the CXCL12-CXCR4 axis drives the immune-desert phenotype in small cell lung cancer by recruiting immunosuppressive CXCR4⁺ neutrophils and S100A8⁺ monocytes.","authors":"Peng Zeng, Hai-Feng Li, Wen-Bin Shu, Jing Zhang, Tian-Cheng Zhao, Jun-Wen Hu, Jun-Fu Wang, Cheng Wang, Qing-Yun Lu, Jia-Hui Yang, Yan-Li An, Rong Chen","doi":"10.1136/jitc-2025-013867","DOIUrl":"10.1136/jitc-2025-013867","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited responses to immunotherapy, largely due to its uniquely immunosuppressive tumor microenvironment (TME). However, the molecular mechanisms driving this phenotype remain incompletely understood.</p><p><strong>Methods: </strong>We integrated single-cell RNA sequencing and Xenium in situ spatial transcriptomics to analyze the immune microenvironment of five SCLC and four non-small cell lung cancer (NSCLC) samples. Multiplex immunofluorescence was used to validate cell types and gene expression in the same tissue specimens, and animal models were employed to verify the key mechanistic pathway.</p><p><strong>Results: </strong>SCLC displayed a distinct immune landscape compared with NSCLC, with increased infiltration of C-X-C motif chemokine receptor 4 (CXCR4)⁺ neutrophils (via neutrophil extracellular traps) and S100A8⁺ monocytes (toward an M2-like phenotype), and reduced CD8⁺ T-cell infiltration. Malignant epithelial cells in SCLC highly expressed CXCR4, regulated by transcription factors ISL LIM homeobox 1 and distal-less homeobox 5, which promoted immunosuppression. The C-X-C motif chemokine ligand 12 (CXCL12)-CXCR4 axis mediated competitive inhibition, impairing T-cell recruitment while enhancing neutrophil accumulation. Monocytes in SCLC shifted toward an M2-like phenotype, weakening antigen presentation. Xenium spatial transcriptomics confirmed colocalization of CXCR4⁺ neutrophils and S100A8⁺ monocytes with tumor cells at the tumor-normal interface, while CD8⁺ T cells were spatially segregated. In vivo experiments showed that CXCR4 inhibition reduced SCLC tumor growth, decreased immunosuppressive cell infiltration, and enhanced CD8⁺ T-cell accumulation.</p><p><strong>Conclusions: </strong>The CXCL12-CXCR4 axis, together with immunosuppressive CXCR4⁺ neutrophils and S100A8⁺ monocytes, is a key driver of the immune-desert phenotype in SCLC. Targeting this axis holds promise as a therapeutic strategy to remodel the immunosuppressive TME and improve the efficacy of immunotherapy for SCLC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698740","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":"Ernest C Borden (1939-2026): in memoriam for a life of caring, researching, leading, teaching and serving.","authors":"Paul M Sondel, Joan H Schiller, John M Kirkwood, Michael T Lotze, Howard H Bailey, Christian M Capitini","doi":"10.1136/jitc-2026-015476","DOIUrl":"https://doi.org/10.1136/jitc-2026-015476","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147690189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional immunosuppression and associated systemic markers in focally relapsed sarcomatoid mesothelioma: case report.","authors":"Hely Ollila, Prateek Kulkarni, Hyojin Kim, Pratiti Ankola, Navin K Chintala, Carlos Thomas, Jennifer L Sauter, Michael Offin, Prasad S Adusumilli","doi":"10.1136/jitc-2025-014516","DOIUrl":"10.1136/jitc-2025-014516","url":null,"abstract":"<p><p>A 52-year-old man presented with sarcomatoid diffuse pleural mesothelioma that had relapsed at an isolated site after a complete response to dual-immune checkpoint inhibition (ICI). Targeted sequencing exhibited amplification of chromosome 9p24, encompassing JAK2, PD-L1, PD-L2, and PTPRD in the relapsed (post-ICI) tumor, compared with baseline (pre-ICI). On multiplex immunofluorescence, tumor-associated macrophages (TAMs) and CD8⁺ cytotoxic T lymphocytes (CTLs) made up most of the cells in baseline and relapsed tumor (59% and 47%, respectively). Baseline tumor cells expressed genes linked to extracellular matrix remodeling and epithelial-mesenchymal transition, intermixed with M2-like TAMs and tissue-resident, effector-like CTLs. Relapsed tumor cells shifted to a growth factor-driven phenotype (NT5E, NOD1, GATA2, FN1, PDCD1LG2) that is known to cause functional impairment of CTLs, which then transitioned to an exhausted state (FCRL3, CST7, GPR171, TRAT1, LAG3); exhausted CD8⁺ and CD4⁺ T cells are seen in the peripheral blood at relapse. TAMs were enriched in antigen-presentation (CD80, CD86, CXCL10), extracellular matrix-degradation (MMP9, CTSL), and CTL-suppression (ARG1, PLA2G7) pathways. Our analyses revealed that regional immunosuppression mediated by adaptive reprogramming of tumor-cell and immune-cell (TAMs, CTLs)-intrinsic changes-rather than by immune evasion or stromal exclusion-served as a mechanism of acquired resistance to dual-ICI therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147690151","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":"Non-enzymatic Rnaseh2c orchestrates proliferating macrophage-driven immunosuppression and HCC progression via Cdk9 proliferation axis and CCL2/CCR2-mediated CD8⁺ T_ex infiltration: a novel therapeutic paradigm with \"Rnaseh2c-In1\" inhibitor.","authors":"Zengbin Wang, Ruiying Xiao, Mengxin Liu, Lihua Ceng, Zikun Lin, Xinyu Zheng, Miaoxin Shi, Hong Ye, Linqing Wu, Nanhong Tang","doi":"10.1136/jitc-2026-014993","DOIUrl":"10.1136/jitc-2026-014993","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages are pivotal drivers of hepatocellular carcinoma (HCC) progression. However, the functional contributions of proliferating macrophages (Prolif Ms) within the tumor microenvironment (TME) remain poorly defined.</p><p><strong>Methods: </strong>Here, we integrated single-cell RNA sequencing, Cleavage Under Targets and Tagmentation (CUT&Tag), bulk RNA sequencing, multiparametric immunofluorescence, flow cytometry, and molecular dynamics simulation to dissect the phenotype, functional landscape, and targeting strategy of Prolif Ms in HCC.</p><p><strong>Results: </strong>We identified a novel Prolif Ms subset characterized by high expression of proliferation markers (Cdk1, Mki67), distinct from classical M1/M2 macrophages. Mechanistically, ribonuclease H2 subunit C (Rnaseh2c) acts as a non-enzymatic regulator, binding directly to the cyclin-dependent kinase promoter to drive macrophage proliferation while suppressing endocytic and antigen-presenting capabilities. Rnaseh2c further promotes CD8⁺ exhausted T cell (CD8⁺ T_ex) infiltration via the C-C motif chemokine ligand 2/C-C motif chemokine receptor type 2 (CCL2/CCR2) axis, fostering an immunosuppressive TME. Notably, Rnaseh2c exhibits cancer-promoting effects in both macrophages and hepatocytes. We developed a specific inhibitor \"Rnaseh2c-In1\", which inhibits HCC growth by reducing CCL2 secretion and CD8⁺ T_ex infiltration, demonstrating favorable pharmacokinetics and low toxicity.</p><p><strong>Conclusions: </strong>This study elucidates a non-enzymatic Rnaseh2c-driven mechanism regulating Prolif Ms, providing a novel therapeutic target and candidate compound for HCC treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 4","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147690167","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}