Cgas deficiency promotes tumor growth by supporting B cell persistence and angiogenesis

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.