2. Academic Validation
  3. Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage

Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage

  • Cancer Cell. 2026 Feb 9;44(2):306-320.e7. doi: 10.1016/j.ccell.2025.12.013.
Lei Li 1,  Qi Ye 1,  Jinlu Ma 2,  Zixi Wang 1,  Tianjie Liu 1,  Yuzeshi Lei 1,  Mingming Lu 1,  Jialu Kang 1,  Haohan Xiang 1,  Buyun Li 1,  Shan Xu 1,  Ke Wang 1,  Yule Chen 1,  Jiaqi Chen 1,  Bohan Ma 1,  Wenyue Huang 1,  Mengjiao Cai 2,  Nan Wu 1,  Yanqiang Li 1,  Jiale An 1,  Chongming Jiang 3,  Rui Ye 4,  Jing Liu 1,  Steven H Lin 4,  Yang Gao 5,  Jian Ma 6,  Lei Li 7
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.
  • 2 Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.
  • 3 Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA.
  • 4 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. Electronic address: [email protected].
  • 6 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. Electronic address: [email protected].
  • 7 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. Electronic address: [email protected].
PMID: 41512867 DOI: 10.1016/j.ccell.2025.12.013
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

SPOP mutation; TREX1; cytosolic DNA; immune responses; radiotherapy.

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