Tumors with microsatellite instability upregulate TREX1 to escape antitumor immunity

作者：Yan Xu, Zheqi Zhou, Wen-Zheng Chen, Fei Du, Sanling Huang, Jinhui Qi, Yuwen Zeng, Hao Su, Jiaxin Wang, Chunfu Xiao, Xiaoyu Zhao, Xiaoge Liu, Yang Feng, Chuan‐Yun Li, Fan Wang, Zhaofei Liu, Yunjia Zhang, Zhi Peng, Zhaode Bu, Yang‐Xin Fu, Ziyu Li, Di Wang, Chuanhui Han · 发表于：The Journal of Experimental Medicine · 年份：2025 · DOI：10.1084/jem.20250265 · 被引用次数：4 · 研究领域：interferon and immune responses、Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers

Currently, it remains largely unclear how MSI-H/dMMR tumors, despite heightened immune pathway activation and antigenic mutation accumulation, evade immune elimination and promote tumorigenesis. Our study showed that dMMR tumors accumulate cytosolic double-stranded DNA, activating the cGAS-IFN pathway and upregulating DNA-digesting enzyme TREX1. In immunocompetent mice, Trex1 depletion in MSI-H/dMMR tumors abolished tumor formation in a CD8+ T cell-dependent manner, suggesting its critical role in enabling these tumors to evade immune attack. Mechanistically, Trex1 loss amplified tumor-intrinsic cGAS-STING signaling, promoted the activation of CD8+ T cells, and triggered systemic antitumor immunity. Critically, ablating cGAS-STING signaling in MSI-H/dMMR tumors abolished the immune boost from TREX1 deletion, revealing the critical role MSI-H/dMMR tumor-intrinsic cGAS-STING pathway. Furthermore, Trex1 inhibition specifically reduced MSI-H/dMMR tumors growth in vivo, highlighting its clinical potential. Together, we identify the cGAS-STING-TREX1 loop as a key immune escape mechanism in MSI-H/dMMR cancers, suggesting TREX1 inhibition could enhance immunotherapy for these patients.