Tumors with microsatellite instability upregulate TREX1 to escape antitumor immunity

  • J Exp Med. 2025 Dec 1;222(12):e20250265. doi: 10.1084/jem.20250265.
Yan Xu  #  1 ,  Zheqi Zhou  #  1  2 ,  Wenzheng Chen  #  1 ,  Fei Du  #  3 ,  Sanling Huang  1 ,  Jinhui Qi  1  2 ,  Yuwen Zeng  2 ,  Hao Su  1 ,  Jiaxin Wang  4 ,  Chunfu Xiao  4 ,  Xiaoyu Zhao  2 ,  Xiaoge Liu  3 ,  Yang Feng  1 ,  Chuan-Yun Li  4 ,  Fan Wang  1 ,  Zhaofei Liu  2 ,  Yunjia Zhang  3 ,  Zhi Peng  1 ,  Zhaode Bu  1 ,  Yang-Xin Fu  5  6 ,  Ziyu Li  1 ,  Di Wang  3 ,  Chuanhui Han  1  2
Affiliations
  • 1. State Key Laboratory of Molecular Oncology, Frontiers Science Center for Cancer Integrative Omics, Peking University Cancer Hospital and Institute, Peking University International Cancer Institute, Peking University Health Science Center , Beijing, China.
  • 2. School of Basic Medical Sciences, Peking University Health Science Center , Beijing, China.
  • 3. BGI Research , Beijing, China.
  • 4. State Key Laboratory of Protein and Plant Gene Research, Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University , Beijing, China.
  • 5. Changping Laboratory , Beijing, China.
  • 6. School of Basic Medical Sciences, School of Medicine, Tsinghua University , Beijing, China.
  • # Contributed equally.
PMID: 41055714 DOI: 10.1084/jem.20250265
Abstract

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.

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