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This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12\/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12\/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12\/13 degradation delayed tumor growth and synergized with anti\u2013PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. 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