Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway is vital for anti-tumor immunity, but its role in tumor vasculature is unclear. Herein, using preclinical liver cancer models in Cgas/Sting-deficient male mice, we report that the interdependence between tumor cGAS and host STING mediates vascular normalization and anti-tumor immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates tumor cGAS expression and produces cGAMP. Subsequently, cGAMP is transported via LRRC8C channels to activate STING in endothelial cells, enhancing recruitment and transendothelial migration of lymphocytes. In vivo studies in male mice also reveal that administration of vitamin C, a promising anti-cancer agent, stimulates TET2 activity, induces tumor vascular normalization and enhances the efficacy of anti-PD-L1 therapy alone or in combination with IL-2. Our findings elucidate a crosstalk between tumor and vascular endothelial cells in the tumor immune microenvironment, providing strategies to enhance the efficacy of combinational immunotherapy for liver cancer.

诱导肿瘤血管正常化是增强免疫治疗疗效的关键措施。 cGAS-STING 通路对于抗肿瘤免疫至关重要，但其在肿瘤血管系统中的作用尚不清楚。在此，我们使用Cgas / Sting缺陷雄性小鼠的临床前肝癌模型，报告肿瘤 cGAS 和宿主 STING 之间的相互依赖性介导血管正常化和抗肿瘤免疫反应。从机制上讲，TET2 介导的 IL-2/STAT5A 信号在表观遗传上上调肿瘤 cGAS 表达并产生 cGAMP。随后，cGAMP 通过 LRRC8C 通道转运，激活内皮细胞中的 STING，增强淋巴细胞的募集和跨内皮迁移。对雄性小鼠的体内研究还表明，给予维生素 C（一种有前景的抗癌剂）可刺激 TET2 活性，诱导肿瘤血管正常化，并增强单独或与 IL-2 联合使用的抗 PD-L1 疗法的疗效。我们的研究结果阐明了肿瘤免疫微环境中肿瘤和血管内皮细胞之间的串扰，为增强肝癌联合免疫治疗的疗效提供了策略。