{"title":"Cgas deficiency promotes tumor growth by supporting B cell persistence and angiogenesis.","authors":"Papasara Chantawichitwong, Sarinya Kumpunya, Tossapon Wongtangprasert, Peerapat Visitchanakun, Trairak Pisitkun, Prapaporn Pisitkun","doi":"10.1016/j.cellimm.2025.105036","DOIUrl":null,"url":null,"abstract":"<p><p>The cGAS sensor activates the STING/IFN signaling pathway, which is crucial for antiviral and antitumor responses. This study aims to investigate the cGAS-mediated immune responses in tumorigenesis using the MC-38 tumor model. MC38-tumor models were established in wild-type (WT) and Cgas-deficient mice to investigate immunophenotypes and cellular mechanisms involved in tumor progression. Cgas<sup>-/-</sup> mice exhibited significantly larger tumors and reduced survival compared to WT mice. Tumors in Cgas<sup>-/-</sup> mice showed increased fibrosis and neovascularity. WT mice mounted a more robust T-cell-mediated antitumor response, with higher levels of NK and effector T cells, while Cgas<sup>-/-</sup> mice showed an expansion of B cells, including regulatory B cells producing IL-10. B cells from tumor-bearing Cgas<sup>-/-</sup> mice demonstrated enhanced survival in the tumor-conditioned medium than those from WT mice. B cell depletion significantly reduced tumor size in WT mice but had minimal effect in Cgas<sup>-/-</sup> mice, where fibrosis and tumor vasculature persisted. Notably, despite B cell depletion, B cells remained in the tumors of Cgas<sup>-/-</sup> mice, in contrast to WT mice, where depletion correlated with increased CD8<sup>+</sup> T cell infiltration. Upregulation of Tgfb1, Tlr7, Tlr9, and Tnfrsf13c in tumors of Cgas<sup>-/-</sup> mice suggested a tumor microenvironment (TME) that promotes B cell survival. Furthermore, Cgas<sup>-/-</sup> B cells promoted angiogenesis, as indicated by enhanced endothelial tube formation. cGAS deficiency fosters tumor growth by reducing the antitumor response, promoting a pro-tumor microenvironment, and supporting B cell survival. The Cgas<sup>-/-</sup> B cells enhance angiogenesis and are resistant to B cell depletion, contributing to tumor progression.</p>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"418 ","pages":"105036"},"PeriodicalIF":2.9000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.cellimm.2025.105036","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The cGAS sensor activates the STING/IFN signaling pathway, which is crucial for antiviral and antitumor responses. This study aims to investigate the cGAS-mediated immune responses in tumorigenesis using the MC-38 tumor model. MC38-tumor models were established in wild-type (WT) and Cgas-deficient mice to investigate immunophenotypes and cellular mechanisms involved in tumor progression. Cgas-/- mice exhibited significantly larger tumors and reduced survival compared to WT mice. Tumors in Cgas-/- mice showed increased fibrosis and neovascularity. WT mice mounted a more robust T-cell-mediated antitumor response, with higher levels of NK and effector T cells, while Cgas-/- mice showed an expansion of B cells, including regulatory B cells producing IL-10. B cells from tumor-bearing Cgas-/- mice demonstrated enhanced survival in the tumor-conditioned medium than those from WT mice. B cell depletion significantly reduced tumor size in WT mice but had minimal effect in Cgas-/- mice, where fibrosis and tumor vasculature persisted. Notably, despite B cell depletion, B cells remained in the tumors of Cgas-/- mice, in contrast to WT mice, where depletion correlated with increased CD8+ T cell infiltration. Upregulation of Tgfb1, Tlr7, Tlr9, and Tnfrsf13c in tumors of Cgas-/- mice suggested a tumor microenvironment (TME) that promotes B cell survival. Furthermore, Cgas-/- B cells promoted angiogenesis, as indicated by enhanced endothelial tube formation. cGAS deficiency fosters tumor growth by reducing the antitumor response, promoting a pro-tumor microenvironment, and supporting B cell survival. The Cgas-/- B cells enhance angiogenesis and are resistant to B cell depletion, contributing to tumor progression.
期刊介绍:
Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered.
Research Areas include:
• Antigen receptor sites
• Autoimmunity
• Delayed-type hypersensitivity or cellular immunity
• Immunologic deficiency states and their reconstitution
• Immunologic surveillance and tumor immunity
• Immunomodulation
• Immunotherapy
• Lymphokines and cytokines
• Nonantibody immunity
• Parasite immunology
• Resistance to intracellular microbial and viral infection
• Thymus and lymphocyte immunobiology
• Transplantation immunology
• Tumor immunity.