Ubiquitination-Directed Cytosolic DNA Degradation Governs cGAS-Sting-Mediated Immune Response to DNA Damage

Authors

Lei Li
Qi Ye
Jinlu Ma
Zixi Wang
Tianjie Liu
Yuzeshi Lei
Mingming Lu
Jialu Kang
Haohan Xiang
Buyun Li
Shan Xu
Ke Wang
Yule Chen
Jiaqi Chen
Bohan Ma
Wenyue Huang
Mengjiao Cai
Nan Wu
Yanqiang Li
Jiale An
Chongming Jiang
Rui Ye
Jing Liu
Steven H Lin
Yang Gao
Jian Ma
Lei Li

Language

English

Publication Date

2-9-2026

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.12.013

PMID

41512867

Abstract

Activation of cGAS-STING signaling in cancer cells requires cytosolic DNA produced by intrinsic or treatment-induced DNA damage. However, clinical efforts to exploit this pathway to improve immunotherapy have yielded limited success, highlighting gaps in understanding the link between DNA damage and immunotherapy. Here, we identify ubiquitination-directed cytosolic DNA degradation as a critical determinant for cGAS-STING activation following DNA damage. Mechanistically, the cytosolic DNA exonuclease TREX1 is degraded by the E3 ubiquitin ligase SPOP but is reversely stabilized by the deubiquitinase USP7. Cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and impairing cGAS-STING-mediated immune activation. Notably, elevated USP7 expression correlates with reduced tumor-infiltrating lymphocytes and accelerated disease progression in patients undergoing chemoradiotherapy. Furthermore, USP7 inhibitors reduce TREX1 levels and restore immune responses following radiation. These findings elucidate the mechanisms linking DNA damage to immune activation and highlight USP7 inhibitors as potential enhancers of radioimmunotherapy.

Keywords

Humans, Nucleotidyltransferases, DNA Damage, Ubiquitination, Membrane Proteins, Exodeoxyribonucleases, Ubiquitin-Specific Peptidase 7, Cytosol, Phosphoproteins, Mice, Animals, Signal Transduction, Cell Line, Tumor, Nuclear Proteins, Neoplasms, HEK293 Cells, STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, SPOP mutation, TREX1, cytosolic DNA, immune responses, radiotherapy

Published Open-Access

yes

Recommended Citation

Li, Lei; Ye, Qi; Ma, Jinlu; et al., "Ubiquitination-Directed Cytosolic DNA Degradation Governs cGAS-Sting-Mediated Immune Response to DNA Damage" (2026). Faculty, Staff and Student Publications. 6169.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6169