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

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…

• NN
  National Natural Science Foundation of China

  Awards: 82422053, 82173037, 82230097, 82222049
• NS
  National Science and Technology Major Project
• NK
  National Key Research and Development Program of China
• NM
  National Major Science and Technology Projects of China

  Awards: 2025ZD0544800, 2025ZD0544802
• NK
  National Key Research and Development Program of China Stem Cell and Translational Research

  Awards: 2023YFC3404100, 2023YFC3404104