Cancer immunology research最新文献

{"title":"Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome.","authors":"Alex Chen, Jose S Pulido, Jason Tonne, Muriel Metko, Jill M Thompson, Thanich Sangsuwannukul, Maria P Chiriboga-Yerovi, Rosa M Diaz, Mason J Webb, Amanda L Huff, Madelyn Moore, Matthew R Schuelke, Sheeba Irshad, Elizabeth Appleton, Alan Melcher, Benjamin Kendall, Richard G Vile","doi":"10.1158/2326-6066.CIR-25-1589","DOIUrl":"10.1158/2326-6066.CIR-25-1589","url":null,"abstract":"<p><p>T-cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue-specific self-antigens for presentation to naïve T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of \"selfness\" at the RNA and protein levels which, when presented on major histocompatibility complexes, shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by re-setting the immunological selfness of cancer cells, this AIRE-mediated immunotherapy 1) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; 2) conferred upon non-immunogenic tumors de novo sensitivity to immune checkpoint blockade; 3) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and 4) lead to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors. Patient RNA-sequencing data showed that expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting our studies have therapeutic translational value.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817487","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":"Targeting ERO1A enhances antitumor immune response by recruiting CD8+T cells and synergizing with PD-L1 blockade in liver cancer.","authors":"Jing Mao, Xu Sun, Caiyun Chu, Yujiu Liang, Jian Chu, Yinhang Wu, Shuwen Han","doi":"10.1158/2326-6066.CIR-25-1471","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1471","url":null,"abstract":"<p><p>Despite the availability of various treatment modalities for liver cancer, its mortality rate remains high. Immunotherapy represents an emerging approach for liver cancer. However, the response rate to single-agent immune checkpoint blockade therapy is suboptimal. Endoplasmic reticulum oxidoreductase 1-alpha (ERO1A), a potential therapeutic target associated with endoplasmic reticulum (ER) stress, is implicated in impeding protective antitumor immunity. In this study, we found that targeting ERO1A in liver cancer, while activating the PERK/EIF2α/ATF4/CHOP-mediated apoptosis and autophagy signaling, downregulated ADORA1 and inhibited the cGMP/PKG pathway, thereby promoting the expression and secretion of CCL4. This led to an increased infiltration of CD8+T cells into the immune microenvironment, enhancing the antitumor immune response. Furthermore, targeting ERO1A in liver cancer also upregulated type I interferon synthesis, activated the JAK-STAT pathway, and promoted programmed cell death ligand 1 (PD-L1) and MHC-Ⅰ expression. Using liver cancer animal models, we demonstrated that combination treatment with ERO1A inhibitor and PD-L1 inhibitor increased CD8+T cell infiltration and enhanced their function within the tumor microenvironment, resulting in synergistic antitumor effects. Therefore, ERO1A represents a promising therapeutic target in liver cancer, potentially suitable for combination with immune checkpoint inhibitors to improve patient outcomes.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817557","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":"MERTK inhibition cooperates with immunomodulatory cyclophosphamide to induce CXCL9⁺ monocyte-macrophage programming and durable antitumor immunity in triple negative breast cancer.","authors":"Alex J Smith, Zachary Schrank, Nan Guan, Diego A Pedroza, Sebastian J Calderon, Xueying Yuan, Na Zhao, Zoe Gabriel, Yang Gao, Charlotte H Rivas, Fengshuo Liu, Jonathan S Serody, Charles M Perou, H Shelton Earp, Jeffrey M Rosen","doi":"10.1158/2326-6066.CIR-26-0278","DOIUrl":"10.1158/2326-6066.CIR-26-0278","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) has high rates of recurrence despite chemotherapy and immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) can either suppress or support antitumor immunity, but the mechanisms governing these states and therapeutic targets remain unclear. Here, integrating public scRNAseq datasets with TNBC cohorts, we identify a prognostic myeloid signature defined by CXCL9hi programs, associated with improved survival and enrichment of lymphocyte activation pathways. Using immunocompetent p53-null syngeneic TNBC models spanning basal-like (2153L) and claudin-low (T12) subtypes, we show that immunomodulatory cyclophosphamide (CTX) reprograms hematopoiesis toward the monocytic lineage and induces an interferon (IFN) conditioned tumor milieu that supports CXCL9⁺ monocyte-derived macrophages (Mo.Macs) in basal-like disease. Combining CTX with the next generation MERTK-selective inhibitor UNC2371 (MRX-2843) drives complete remission in both models, but durable long-term responses occurred selectively in the basal-like subtype model. Antigen-presenting CXCL9⁺ Mo.Macs expand and C1Q⁺ TAMs are reduced in responding tumors. Mechanistically, MERTK inhibition relieves MAPK/SOCS1 mediated restraint of IFN signaling driving CXCL9 induction. Functionally, tumor control requires CXCL9-CXCR3 dependent CD4⁺ T cell recruitment and correlates with the accumulation of stem-like memory CD4⁺ T cells, and germinal center-associated lymphoid organization in tumor-draining lymph nodes. PD-1 blockade further increases durability, preventing recurrence in most treated basal-like tumors. Together, these findings define an IFN licensed, MERTK regulated myeloid checkpoint that can be therapeutically targeted to convert suppressive TNBC microenvironments into durable adaptive immunity, supporting clinical translation of CTX + MRX-2843 based combinations in basal-like TNBC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788612","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":"TIM3 blockade with hypomethylating therapy restores NK-cell and cytotoxic CD4+ T-cell activity in patients with AML or MDS.","authors":"Jani Huuhtanen, Sofia Forstén, Brittany Ford, Johannes Smolander, Oscar Brück, Sofie Lundgren, Anna Kreutzman, Olli Dufva, Matti Kankainen, Mette Ilander, Hanna Lähteenmäki, Tiina Kasanen, Jay Klievink, Judith Leitner, Peter Steinberger, Mika Kontro, Marc R Pelletier, Harri Lähdesmäki, Catherine Sabatos-Peyton, Mikael L Rinne, Kimmo Porkka, Karita Peltonen, Satu Mustjoki","doi":"10.1158/2326-6066.CIR-26-0160","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0160","url":null,"abstract":"<p><p>Occasional complete responses to immune checkpoint inhibitor therapy demonstrate that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be immune-sensitive when appropriately targeted. Here, we analyzed AML/MDS patients (n=14) treated with the anti-TIM3 sabatolimab and the hypomethylating agent decitabine in a phase Ib clinical trial (NCT03066648) using single-cell RNA and T cell receptor (TCR) sequencing (n=6) and functional co-culture assays. Unlike T cell-restricted CTLA4 and PD1, TIM3 was broadly expressed across natural killer (NK)-cell, myeloid-cell, and T-cell populations. Therapy induced expansion of cytotoxic NK-cell subsets and enhanced type I interferon signaling. Fewer than 1% of bone marrow CD8+ T cells displayed a canonical exhaustion phenotype, and treatment preferably expanded small CD8+ T-cell clones in responders. Responders exhibited greater expansion of cytotoxic CD4+ T cells and B cells, as exemplified by a patient with pre-existing CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) achieving an outstanding complete response lasting 23 months. Over 20% of this patient's lymphocytes were T-LGLL cells expressing a TCR capable of recognizing autologous blasts. Overall, our results suggest that anti-TIM3 combined with decitabine engages a distinct mechanism of immune activation compared to anti-PD1 and anti-CTLA4, preferentially expanding NK-cell and CD4+ T-cell populations.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759833","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":"Single-cell profiling of peripheral blood mononuclear cells in diverse men with prostate cancer reveals a fatal disease-associated immune signature.","authors":"Huaitian Liu, Alexandra R Harris, Tiffany H Dorsey, Md Shakir Uddin Ahmed, Ashlie Santaliz Casiano, Michael C Kelly, Clayton C Yates, Stefan Ambs","doi":"10.1158/2326-6066.CIR-26-0126","DOIUrl":"10.1158/2326-6066.CIR-26-0126","url":null,"abstract":"<p><p>Alterations in peripheral immunity may contribute to fatal prostate cancer and the excessive disease burden among African American (AA) men. Thus, we investigated peripheral immunity in prostate cancer patients in association with disease outcome and AA descent. We performed single-cell RNA and T cell receptor (TCR) sequencing using peripheral blood mononuclear cells (PBMC) from a cohort of 43 prostate cancer patients with survival follow-up and 16 healthy controls. Analyzing 273,229 high-quality PBMC, we observed that men who developed fatal prostate cancer (n=20) distinctively expressed the LAG3 and TIGIT exhaustion markers in their CD8⁺ T effector memory cells (CD8 TEM). These men also showed a loss of type-2 conventional dendritic cells (cDC2). Further analyses revealed additional transcriptome-inferred functional differences in cDC2, CD16+ monocytes, and CD8 TEM comparing men with and without fatal disease. Those describe cDC2 as immunosuppressed, CD16+ monocytes as pro-inflammatory but less cytotoxic, and CD8 TEM as chronically activated in patients with fatal disease. Comparing AA with European American patients, we observed upregulated LAG3 and TIGIT in AA PBMC. For cDC2 and CD16+ monocytes, fatal disease and AA patients showed shared marker expression. Furthermore, TCR profiling discovered over-representation of large, hyperexpanded clonotypes and a lower TCR diversity among fatal disease and AA patients. Lastly, the CD8 TEM functional status and LAG3 expression in PBMC emerged as a candidate predictor of disease fatality. We conclude that peripheral immunity may distinctly vary in association with disease outcome and AA descent of prostate cancer patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720221","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":"Immune checkpoint blockade sensitivity is linked to endogenous retroelement transcriptional changes in cancer.","authors":"Mercedes Herrera, Sajid A Marhon, Zhihui Amy Liu, Helen Loo, Farnoosh Abbas-Aghababazadeh, Jeff P Bruce, David Chen, Emily Van de Laar, Helen Chow, Philippe L Bedard, Albiruni R Abdul Razak, Anna Spreafico, Marcus O Butler, Stephanie Lheureux, Trevor J Pugh, Benjamin Haibe-Kains, Lillian L Siu, Daniel D De Carvalho, Pavlina Spiliopoulou","doi":"10.1158/2326-6066.CIR-26-0365","DOIUrl":"10.1158/2326-6066.CIR-26-0365","url":null,"abstract":"<p><p>Endogenous retrotransposable elements (EREs) can modulate immune responses. We explored ERE transcription in relation to response to immune checkpoint inhibition in advanced solid tumors. ERE expression was measured in pre and on-treatment samples from patients treated in a clinical trial with pembrolizumab. We evaluated immune cell infiltration and correlated ERE expression with interferon-stimulated gene profiles and cytolytic activity. Two independent datasets were retrospectively analyzed as external validation. ERE transcription, notably Alu followed by LINE elements, is upregulated in immunotherapy responders, and higher ERE expression correlates with durable clinical benefit and improved long-term outcomes. In responders, this dynamic increase correlates with CD8+ T cell infiltration and cytolytic activity, particularly during treatment. A trend towards increased A-to-I RNA editing was observed in responders. External validation in melanoma and non-small cell lung cancer cohorts confirmed a consistent pattern in ERE transcription. Therefore, ERE transcription is as a potential biomarker for personalized immunotherapy in solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148721554","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":"The pre-treatment tumor microenvironment immune status determines Bacillus Calmette-Guerin immunotherapy response in early-stage bladder cancer.","authors":"Yufeng Guo, Xuezhao Ren, Ze Zhang, Hui Cheng, Jin-Peng Ma, Hong Yan, Qian Niu, Xinyu Zhang, Luyang Zhang, Junqiang Tian, Zhilong Dong, Hanzhang Wang, Liang Cheng, Yong-Jie Lu, Zhiping Wang","doi":"10.1158/2326-6066.CIR-25-1445","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1445","url":null,"abstract":"<p><p>Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy for early-stage bladder cancer (BCa), based on its immunostimulatory activity. However, over half of patients experience BCG failure and subsequent recurrence. The heterogeneity of the tumor microenvironment may influence BCG response, however this relationship is currently not well-established. We found that BCG response did not correlate with the number of tumor-infiltrating T cells but was determined by the pre-treatment immunosuppressive microenvironment. We identified a subset of cancer-associated fibroblasts characterized by microfibrillar-associated protein 2 (MFAP2+ CAF), which impaired BCG-induced antitumoral immunity by interacting with both individual T cells and tertiary lymphoid structures/lymphoid aggregates. This study also revealed a potential stepwise activation of cancer immune evasion factors based on cross-sectional analysis, from increasing MFAP2+ CAF to activation of PD-L1 and then LAG3 on T cells, during early-stage BCa development. These findings have the potential to enable accurate prediction of BCG response. This approach may also be applicable to the investigation of other human cancers.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705419","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":"H2AFY2 suppresses exhaustion and enhances antitumor activity of CAR-T cells through transcriptional and epigenetic modifications.","authors":"Congcong Li, Qian Wang, Qitai Zhao, Qianfeng Cai, Siyang Wang, Yu Ping, Xuan Zhao, Xinfeng Chen, Chunyi Shen, Haiming Qin, Guohui Qin, Jiqi Shan, Zhen Zhang, Yi Zhang","doi":"10.1158/2326-6066.CIR-25-1334","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1334","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell exhaustion constitutes a critical barrier to sustained antitumor efficacy. Through transcriptomic analysis of CAR-T cells from patients with lymphoma, we identified the histone variant macroH2A2 (H2AFY2) as a critical regulator of T cell exhaustion-a finding consistently observed across multiple tumor models. In mice, T cell-specific knockout of H2afy2 promots the expression of inhibitory receptors by activating the nuclear factor kappa-B pathway and increasing chromatin accessibility at the Rela locus, as demonstrated by single-cell RNA-sequencing and assay for transposase-accessible chromatin sequencing. H2AFY2 overexpression in CD8+ T cells induces prominent epigenetic remodeling, characterized by increased H3K27me3 enrichment. Mechanistically, H3K27me3 enrichment at the Rela locus suppresses p65-mediated transcriptional activation, leading to downregulation of the exhaustion-associated transcription factor TOX and consequent amelioration of T cell exhaustion. Furthermore, H2AFY2-overexpressing CAR-T cells sustain lower levels of inhibitory receptors and suppressed tumor recurrence. Collectively, these results define an epigenetic pathway through which H2AFY2 counteracts T cell exhaustion and support the therapeutic potential of H2AFY2-engineered CAR-T cells across tumor types.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705383","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":"Targeting CCR1 Remodels the Tumor Microenvironment and Relieves Immunosuppression in Pancreatic Cancer.","authors":"Yaqing Zhang, Padma Kadiyala, Wei Yan, Kristee Brown, Faith R Avritt, Katelyn L Donahue, Megan C Procario, Jude O Okoye, Thejaswini Giridharan, Ahmed M Elhossiny, Carlos E Espinoza, Dominik Awad, Emily L Lasse Opsahl, Paola I Medina-Cabrera, Ashley Velez-Delgado, Rosa E Menjivar, Olivia A Yang, Sion Yang, Xi He, Shruti Gupta, Rahma Tariq, Anona R Brandt, Xinyu Wang, Aaron denDekker, Zeribe C Nwosu, Eileen S Carpenter, Adam H Courtney, Filip Bednar, Timothy L Frankel, Costas A Lyssiotis, Bin Zheng, Ilona Kryczek, Marina Pasca di Magliano","doi":"10.1158/2326-6066.CIR-25-1300","DOIUrl":"10.1158/2326-6066.CIR-25-1300","url":null,"abstract":"<p><p>A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid cell-driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor-infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the functional role of CCR1, we generated oncogenic KRAS-based genetically engineered mouse models of pancreatic cancer, with or without the addition of a mutant form of the tumor suppressor Trp53 (KC and KPC, respectively), lacking CCR1 expression. CCR1 inactivation did not affect the formation of early lesions but delayed progression to cancer and resulted in prolonged survival. In these mice, macrophages lacking CCR1 had reduced expression of the immunosuppressive marker arginase 1. Loss of CCR1 also profoundly shifted the prevalent fibroblast population, inducing a pancreatic stellate cell-like phenotype. In two independent syngeneic orthotopic models, ablation or pharmacologic inhibition of CCR1 reduced tumor growth and increased CD8+ T-cell cytotoxic activity, sensitizing tumors to immunotherapy. Our data show that CCR1-expressing myeloid cells promote pancreatic cancer growth through modulation of the immune microenvironment and fibroblasts, indicating that CCR1 might be a suitable target for combination therapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1233-1253"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13429029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052802","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":"Hypoxia-Induced ADAM8+ Macrophages and FAP+ Fibroblasts Form an Extracellular Matrix-Remodeling Niche at the Tumor Boundary in HCC.","authors":"Qian Jian, Yufeng Li, Weiqi Duan, Jiajin Yang, Zhuomeng Zheng, Qingyu Xie, Jianfeng Yu, Bo Sun, Youcai Deng, Liuqin He, Sulai Liu","doi":"10.1158/2326-6066.CIR-25-1240","DOIUrl":"10.1158/2326-6066.CIR-25-1240","url":null,"abstract":"<p><p>In hepatocellular carcinoma (HCC), stromal and immune components shape invasion and metastasis. To identify the cellular states that drive extracellular matrix (ECM) remodeling, define their organization at the tumor margin, and evaluate their association with prognosis, we profiled stromal regions at the tumor margin using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and multiplex immunofluorescence. Across scRNA-seq profiles from 79 patients, we identified a hypoxia-associated population of tumor-associated macrophages with high expression of a disintegrin and metalloproteinase domain 8 (ADAM8) and upregulation of ECM remodeling programs. ST and histology placed these ADAM8+ macrophages in stromal regions with disorganized collagen. They were often in hypoxic zones around necrosis and adjacent to FAP+ fibroblasts. Ligand-receptor analysis predicted engagement of the collagen-CD44 axis between the two cell types. In vitro, hypoxia induced expression of ADAM8 in macrophages. ADAM8 knockdown reduced the induction of TNFα, IL6, and IL1β and weakened the ability of macrophages to activate fibroblasts. In tissue microarrays, a higher fraction of ADAM8+ macrophages among CD68+ cells predicted shorter overall and recurrence-free survival. Consistently, in a murine HCC model, pharmacologic inhibition of ADAM8 decreased FAP+ fibroblast abundance. Overall, the data show that ADAM8+ macrophages and FAP+ fibroblasts form a hypoxia-linked ECM remodeling niche at the tumor boundary. This stromal remodeling unit associates with poor prognosis and suggests testable targets for stroma-focused therapy for HCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1254-1271"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926395","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}