Although cGAS-STING–mediated DNA sensing in tumor cells or phagocytes is central for launching antitumor immunity, the role of intrinsic cGAS-STING activation in T cells remains unknown. Here, we observed that peripheral blood CD8⁺ T cells from patients with cancer showed remarkably compromised expression of the cGAS-STING cascade. We demonstrated that the cGAS-STING cascade in adoptively transferred CD8⁺ T cells was essential for antitumor immune responses in the context of T cell therapy in mice. Mechanistically, cell-autonomous cGAS and STING promoted the maintenance of stem cell–like CD8⁺ T cells, in part, by regulating the transcription factor TCF1 expression. Moreover, autocrine cGAS-STING–mediated type I interferon signaling augmented stem cell–like CD8⁺ T cell differentiation program mainly by restraining Akt activity. In addition, genomic DNA was selectively enriched in the cytosol of mouse CD8⁺ T cells upon in vitro and in vivo stimulation. STING agonism enhanced the formation of stem-like central memory CD8⁺ T cells from patients with cancer and potentiated antitumor responses of CAR-T cell therapy in a xenograft model. These findings advance our understanding of inherent cGAS-STING activation in T cells and provide insight into the development of improved T cell therapy by harnessing the cGAS-STING pathway for cancer immunotherapy.

尽管cGAS-STING介导的肿瘤细胞或吞噬细胞中的DNA传感对于启动抗肿瘤免疫至关重要，但内在性cGAS-STING激活在T细胞中的作用仍然未知。在这里，我们观察到癌症患者的外周血CD8 ⁺ T细胞显示出cGAS-STING级联的表达明显受损。我们证明过继转移的CD8 ⁺ T细胞中的cGAS-STING级联对于小鼠T细胞治疗中的抗肿瘤免疫反应至关重要。从机制上讲，细胞自主cGAS和STING促进了干细胞样CD8 ⁺的维持T细胞部分通过调节转录因子TCF1的表达。此外，自分泌cGAS-STING介导的I型干扰素信号传导主要通过抑制Akt活性来增强干细胞样CD8 ⁺ T细胞分化程序。另外，在体外和体内刺激后，基因组DNA选择性地富集在小鼠CD8 ⁺ T细胞的细胞质中。STING激动作用增强了来自癌症患者的干样中央记忆CD8 ⁺ T细胞的形成，并在异种移植模型中增强了CAR-T细胞疗法的抗肿瘤反应。这些发现提高了我们对T细胞固有cGAS-STING活化的理解，并通过利用cGAS-STING途径进行癌症免疫治疗为改进的T细胞疗法的发展提供了见识。