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.
© 2025 Xu et al.