Cancer immunology research最新文献

{"title":"Targeted TNF Potentiates the Activity of Bispecific T-cell Engagers in Solid Tumors by Turning Cold Tumors Hot.","authors":"Gudrun Thorhallsdottir, Ramon Benz, Pinuccia Faviana, Francesco Bartoli, Natascia Leonardi, Ivann Sekielyk, Laura Fetriconi, Samuele Cazzamalli, Emanuele Puca, Dario Neri, Abdullah Elsayed","doi":"10.1158/2326-6066.CIR-25-1572","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1572","url":null,"abstract":"<p><p>Colorectal cancer remains a major global health burden and an area of urgent unmet medical need. Immunotherapy has shown limited success in colorectal cancer as most patients present with an immune-excluded, \"cold\" tumor microenvironment (TME). In this study, we report a dual-modality approach to treating colorectal cancer by combining the tumor necrosis factor (TNF)-based fusion protein directed to the extradomain B (EDB) of fibronectin, L19-TNF, which induces localized intratumoral inflammation and facilitates T-cell infiltration, with a CD3-based bispecific T-cell engager (TCE) targeting carcinoembryonic antigen (CEA), which mediates antigen-specific cytotoxicity. Together, these agents aim to remodel the TME, convert \"cold\" tumors into inflamed \"hot\" lesions, and broaden the therapeutic reach of immunotherapy in colorectal cancer. Immunohistochemistry confirmed coexpression of CEA and EDB across microsatellite-stable and -instable tumors. In vitro, L19-TNF in combination with a CEAxCD3 TCE significantly enhanced tumor cell killing and CD8+ T-cell proliferation. In vivo, the combination induced complete tumor regression in most animals, prolonged survival, and conferred durable protection against tumor rechallenge. Furthermore, mechanistic analyses revealed enhanced TCE extravasation, upregulated intercellular adhesion molecule 1 expression, and increased CD8+ T-cell infiltration, indicating vascular modulation and remodeling of the TME toward an inflamed \"hot\" phenotype. These findings confirm that targeted delivery of TNF to the TME can effectively enhance the activity of immunotherapeutic agents, such as T cell-redirecting therapies, in challenging tumor settings.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"OF1-OF14"},"PeriodicalIF":8.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763223","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":"ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion.","authors":"Sujit Kashyap, Jun Hyung Sin, Sophia M Guldberg, Jacqueline L Yee, Maya Lopez-Ichikawa, Sloan H Phillips, Matthew H Spitzer, Michael Waterfield","doi":"10.1158/2326-6066.CIR-25-0816","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0816","url":null,"abstract":"<p><p>CD8+ T cell exhaustion limits the immune response to tumors because of ineffective T cell effector functions. Thus, therapies that inhibit T-cell exhaustion are critical for optimizing cancer treatment. Recent studies have implicated epigenetic proteins in T-cell exhaustion. Here, we identified activating transcription factor 7 interacting protein (ATF7ip) as an epigenetic protein critical for inducing T cell exhaustion. Loss of Atf7ip in CD8+ T cells resulted in decreased terminal exhaustion and increased numbers of progenitor-exhausted cells in both chronic viral infections and cancer. Given the decreased T cell terminal exhaustion observed with Atf7ip-deficiency in CD8+ T cells, this may be one mechanism that leads to decreased tumor burden. Mechanistically, ATF7ip functions to stimulate the deposition of repressive H3K9me3 at critical immune-effector gene loci, such as Il7r and Il2 leading to enhanced exhaustion. Our data suggest that ATF7ip may be a rational target for deletion in adoptive T-cell therapies to reduce CD8+ T-cell exhaustion.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670517","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":"Tumor-infiltrating platelets recruit neutrophils to promote tumor growth through the 5-HIAA-GPR35-ERK1/2 axis in Hepatocellular Carcinoma.","authors":"Ning Li, Peng-Cheng Wang, Jing-Yue Pan, Ye Xu, Yu-Hang Ye, Rong-Qi Sun, Si-Yuan Pan, Ya-Ya Ji, Jian Zhou, Jia Fan, Rong-Xin Chen, Shao-Lai Zhou, Zheng-Jun Zhou","doi":"10.1158/2326-6066.CIR-25-0498","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0498","url":null,"abstract":"<p><p>Tumor-associated neutrophils (TANs) promote tumor growth and metastasis in hepatocellular carcinoma (HCC). Platelets can activate neutrophils and contribute to inflammation and organ damage; however, the relationship between TANs and platelets in HCC remains unclear. We performed multiplex immunohistochemistry and found that tumor-infiltrating platelets and TANs exhibited similar spatial distributions in patient-derived HCC samples. Then, a transwell migration assay demonstrated that supernatants from platelets co-cultured with HCC cells enhanced neutrophil migration in vitro, compared with supernatants from platelets or HCC cells cultured alone. Subsequent metabolomics analysis and in vitro and in vivo validation revealed that platelet-derived 5-HIAA promoted neutrophil migration via GPR35. Furthermore, in Hepa1-6 mouse models of HCC, GPR35+ neutrophils were found to facilitate HCC growth. Analysis of human HCC single-cell RNA-seq data and mouse neutrophil bulk RNA-seq data revealed significant upregulation of the MAPK signaling pathway and pathways associated with neutrophil migration and cytokine production in GPR35+ neutrophils. Finally, in vitro experiments demonstrated that 5-HIAA activated the ERK1/2 pathway, enhanced pro-tumor cytokine production and promoted HCC cell growth via GPR35, all of which were suppressed by the GPR35 inhibitor CID2745687. Together, these data indicate that tumor-infiltrating platelets recruit neutrophils to promote tumor growth through the 5-HIAA-GPR35-ERK1/2 axis in HCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653781","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":"DDR1 Promotes Immune Evasion in Colorectal Cancer by Orchestrating IL-33-Mediated M2-like Polarization of Tumor-Associated Macrophages.","authors":"Xiaofan Duan, Gaoshaer Yeerkenbieke, Yanjun Feng, Mingwang Zhou, Yumei Zhang, Jiuli Zhou, Jin Li","doi":"10.1158/2326-6066.CIR-25-1073","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1073","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with low immunotherapy efficacy due to an immunosuppressive tumor microenvironment in proficient mismatch repair (pMMR) disease, which accounts for most cases of CRC. Herine, we have identified discoidin domain receptor 1 (DDR1) as a key immune evasion driver in syngeneic tumor models. Moreover, intestine-specific Ddr1 knockout suppressed tumorigenesis in AOM/DSS and ApcMin/+ mouse models of CRC, with reduced frequency of M2-like tumor-associated macrophages (TAMs) and increased infiltration of CD8+ T cells. Mechanistically, DDR1 induced p-c-Jun-dependent IL33 transcription to drive M2-like macrophage polarization. Mass spectrometry and immunoprecipitation analyses further revealed that DDR1 interacted with DExD-Box Helicase 21 (DDX21) in the nucleus, which inhibited DDX21 ubiquitination, increasing DDX21 levels, which subsequently enhanced c-Jun phosphorylation. Clinically, elevated DDR1 expression in CRC patients correlated with poor prognosis and was positively associated with DDX21 and p-c-Jun. Furthermore, both DDR1 and DDX21 expression showed positive correlations with M2-like TAM infiltration in patient tissues. Therapeutically, genetic knockout and nanoparticle-delivered siRNA targeting DDR1 significantly enhanced anti-PD-1 treatment efficacy in vivo. Thus, our findings establish DDR1-DDX21-c-Jun-IL-33 as an axis that drives immunosuppression in CRC by regulating TAM polarization and indicate DDR1 as a potential target to improve immunotherapy efficacy in pMMR patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653794","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":"Computational Modeling of Cellular Influence Delineates Functionally Relevant and Distinct Cellular Neighborhoods in Primary and Metastatic Pancreatic Ductal Adenocarcinoma.","authors":"Yeonju Cho, Jae W Lee, Sarah M Shin, Alexei G Hernandez, Xuan Yuan, Jowaly Schneider, Jody E Hooper, Laura D Wood, Elizabeth M Jaffee, Atul Deshpande, Won Jin Ho","doi":"10.1158/2326-6066.CIR-25-0844","DOIUrl":"10.1158/2326-6066.CIR-25-0844","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with liver metastases significantly worsening outcomes. However, features of the tumor microenvironment (TME) that are distinct between primary and metastatic sites remain poorly defined. Cellular neighborhoods within the TME are recognized as functional units that influence tumor behavior. Conventional spatial methods, which assign equal weights to all cells in a region, fail to capture the nuances of cellular interactions. To address this, we report here the development of Functional Cellular Neighborhood (FunCN) quantification, which integrates both the proportion and proximity of surrounding cells. Applying FunCN to PDAC imaging mass cytometry data, we identified neutrophil-enriched interactions in liver metastases compared with primary tumors, correlating with elevated VISTA expression by tumor cells. Additionally, FunCN clusters around CD8+ T cells in the pancreas and liver were associated with higher TIGIT and LAG3, respectively. These findings demonstrate the importance of spatial immune landscapes in PDAC and identify potential therapeutic opportunities.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"571-584"},"PeriodicalIF":8.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12988722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060116","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":"Genomic and Immune Landscape of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Progressing on Anti-PD-1 Treatment.","authors":"Athénaïs van der Elst, Daniel Herrero-Saboya, Lucas Michon, Marie Morfouace, Robin Liechti, Preethi Devanand, Daniel Schulz, Maya Persoons, Sylvie Rusakiewicz, Nils Eling, Paul-Antoine Nicolas, Marie-Sophie Robert, Stéphanie R Tissot, Michelle Daniel, Bernd Bodenmiller, Henoch S Hong, Rachel Galot, Paolo Bossi, Julio Oliveira, Florian Estrade, Caroline Even, Sophie Lucas, Pierre Saintigny, Loredana Martignetti, Céline Lefebvre, Jean-Pascal H Machiels","doi":"10.1158/2326-6066.CIR-25-0979","DOIUrl":"10.1158/2326-6066.CIR-25-0979","url":null,"abstract":"<p><p>Anti-PD-1 therapies improve survival in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), but only a minority of patients achieve durable responses. The mechanisms driving resistance to anti-PD-1 in SCCHN remain poorly understood. Using the IMMUcan multiomics workflow, we characterized the molecular and immune profiles of R/M SCCHN progressing on anti-PD-1 treatment and compared them with an anti-PD-1-naïve cohort. Tumor biopsies from patients with anti-PD-1-resistant SCCHN exhibited significantly more EGFR and MYCL amplifications, along with increased MYC pathway alterations. Transcriptomic and proteomic analyses revealed that anti-PD-1-secondary resistant SCCHN had increased CD8+ T-cell infiltration with higher levels of immune exhaustion markers than primary resistant and naïve SCCHN. Additionally, high beta-2-microglobulin (B2M) expression correlated with greater T-cell infiltration and improved survival following anti-PD-1 therapy. Tumor cell B2M expression was independent of TMB and PD-1L expression, suggesting that B2M expression could serve as an additional biomarker for anti-PD-1 response.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"608-624"},"PeriodicalIF":8.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13044521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156118","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":"Neoadjuvant Endocrine Treatment plus Mammaglobin-A DNA Vaccine Induces Antitumor Immune Responses in the Primary Tumor and Peripheral Blood of Patients with Breast Cancer: Insights from a Phase Ib Clinical Trial.","authors":"Rashmi Mishra, Foluso Ademuyiwa, Yilin Yang, John Herndon, Lijin Li, Cherease Street, Nancy Myers, Ina Chen, Xiuli Zhang, Ian S Hagemann, Feng Gao, Christopher A Miller, Narendra V Sankpal, Joel M Guthridge, Madelyn Carmody, Cynthia X Ma, Rama Suresh, Timothy P Fleming, Caleb Marlin, S Peter Goedegebuure, William E Gillanders","doi":"10.1158/2326-6066.CIR-25-0666","DOIUrl":"10.1158/2326-6066.CIR-25-0666","url":null,"abstract":"<p><p>Tumor-associated antigen (TAA) vaccines are being explored as a strategy to induce antitumor immune responses. Mammaglobin-A (Mam-A) is a TAA expressed in >50% of patients with breast cancer. Previously, we have shown that Mam-A DNA vaccines induce antitumor immune responses in patients with stable metastatic disease. To further evaluate the potential of the Mam-A vaccine, we initiated a phase Ib clinical trial in patients with estrogen receptor-positive breast cancer prior to surgery. Eight patients were assigned to arm 1 (neoadjuvant endocrine therapy alone) and 17 to arm 2 (neoadjuvant endocrine therapy plus Mam-A vaccination); the final analysis included 8 patients from arm 1 and 13 from arm 2. Ex vivo enzyme-linked immunospot (ELISpot) analysis of peripheral blood mononuclear cells demonstrated that Mam-A vaccination induced Mam-A-specific T cells in 8 of 13 patients. Intracellular cytokine staining and Mam-A-specific tetramer staining revealed that vaccine-induced Mam-A-specific T cells included both CD4+ and CD8+ polyfunctional T cells. Finally, high-throughput imaging mass cytometry identified 24 cellular metaclusters with features of tumor, immune, stromal, and endothelial cells and revealed an increased CD8+ T-cell prevalence in the tumor after Mam-A vaccination. In particular, vaccination was associated with the infiltration of PD-1+CD8+ T cells. In addition, postvaccination tumor samples exhibited close spatial interactions between cytotoxic CD8+ T cells (CTL) and Mam-A+ tumor cells and between CTL and antigen-experienced CD4+ T cells. Together, these results suggest that Mam-A DNA vaccination elicits both systemic and intratumoral antitumor immune responses.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"543-558"},"PeriodicalIF":8.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130652","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":"Ex Vivo Immuno-Oncology Platform Reveals Spatial T-cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer.","authors":"Ashwini Sakrepatna Nagaraj, Matilda Salko, Aditi Sirsikar, Ziqi Kang, Erdogan Pekcan Erkan, Elina A Pietilä, Iga Niemiec, Jie Bao, Giovanni Marchi, Angéla Szabó, María Hincapié-Otero, Anastasia Lundgren, Kirsten Nowlan, Sanna Pikkusaari, Anna Kanerva, Johanna Tapper, Riitta Koivisto-Korander, Heini Lassus, Liisa Kauppi, Sampsa Hautaniemi, Anna Vähärautio, Jing Tang, Eliisa Kekäläinen, Ulla-Maija Haltia, Anni Virtanen, Joonas Jukonen, Tuula Salo, Anniina Färkkilä","doi":"10.1158/2326-6066.CIR-25-0743","DOIUrl":"10.1158/2326-6066.CIR-25-0743","url":null,"abstract":"<p><p>Identifying new therapeutic approaches in high-grade serous ovarian cancer (HGSC) requires the development of more accurate preclinical models that replicate the patient-specific tumor and its microenvironment. To address this, we established immunocompetent patient-derived cultures (iPDC) for HGSC, cultured on a physiologically relevant human omentum gel matrix. We developed a high-throughput platform that combines drug testing, histologic analysis, genomic profiling, single-cell studies, and spatial biomarker discovery. Our results from 47 tumors showed that iPDCs recapitulated the tumor genomic and histologic characteristics while also retaining the intratumoral immune cells. The iPDC treatment responses correlated significantly with the patients' clinical treatment responses. Using iPDCs and single-cell RNA sequencing, we identified potentially effective therapeutic options for patients with recurrent HGSC linked to distinct tumor cell states and mechanisms of resistance. High-throughput drug response profiling with single-cell imaging identified ataxia telangiectasia and Rad3-related inhibitor (ATRi) combined with an immunotherapy targeting autotaxin as a promising new combination treatment for HGSC. Using hyperplexed imaging and spatial analysis, we discovered that ATRi responses were associated with significant increases in both intra- and peritumoral T-cell infiltration, particularly in PD-1+ CD8+ T cells. Additionally, the ATRi-induced reactivation of CD8+ T cells was linked to spatial interactions with replication stress-positive tumor cells. Thus, our iPDC platform presents a representative high-throughput ex vivo model to advance precision oncology in HGSC, uncovering the ATRi-immunotherapy combination as a potentially effective therapeutic option for clinical translation.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"625-639"},"PeriodicalIF":8.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7618831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017571","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":"Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T-cell Antitumor Immunity through Metabolic Reprogramming.","authors":"Phaethon Philbrook, Matthew J Dean, Maria Dulfary Sanchez-Pino, Li Qin Zheng, Jovanny Zabaleta, Julio A Vázquez-Martínez, Darwin Chang, Jessica K Mandula, Timothy I Shaw, Dorota Wyczechowska, Jone Garai, Ramesh Thylur Puttalingaiah, Amirsalar Mansouri, Weishan Huang, Satyajit Das, Shiun Chang, José R Conejo-Garcia, Paulo C Rodriguez, Augusto C Ochoa","doi":"10.1158/2326-6066.CIR-25-0695","DOIUrl":"10.1158/2326-6066.CIR-25-0695","url":null,"abstract":"<p><p>G protein-coupled receptor 84 (GPR84) is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T-cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T-cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacologic antagonism with GLPG1205 or genetic deletion of GPR84 promoted T-cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T-cell function and may further enhance adoptive cellular therapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"640-657"},"PeriodicalIF":8.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12990994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008893","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":"Regulatory T-cell Sensing of Extracellular ATP via P2RX7 Promotes Their Accumulation and Suppression and Drives Lung Tumor Growth.","authors":"Igor Santiago-Carvalho, Ronaldo Francisco, Bruna Gois Macedo, Caio Loureiro Salgado, Carly R Stoll, Samantha Shao, Angad Beniwal, Tina Kwok, Alma Banuelos, Marcos Pinheiro Cione, Emily White, Tyler M Johnston, Chloe Liliana Leff, Ildefonso Silva Junior, Fabio Carvalho de Souza, Win Thant, Prita Pandya, Maria Regina D'Império Lima, Sebastian Fernandez-Bussy, David Abia-Trujillo, Linh H Vu, Nhan L Tran, Bryan C Husta, John A Copland, Fotini Gounari, Verline Justilien, Jessica Naomi Lancaster, Henrique Borges da Silva","doi":"10.1158/2326-6066.CIR-25-0567","DOIUrl":"10.1158/2326-6066.CIR-25-0567","url":null,"abstract":"<p><p>Lung cancer is the leading cause of cancer-related deaths worldwide, and despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teff) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Treg), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular adenosine 5-triphosphate receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-knockout (P2RX7-KO) mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared with P2RX7-KO Tregs, which failed to inhibit type 1 and follicular helper T-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared with P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"658-675"},"PeriodicalIF":8.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12927004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017521","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}