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 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.