CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models
Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an immunogenic molecular subtype of prostate cancer, marked by genomic instability and increased intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that CDK12 inactivation or suppression of its paralog CDK13 activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced CDK12/13 expression correlates with improved survival and treatment response. Mechanistically, CDK12/13 depletion or targeted degradation induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, CDK12/13 degradation significantly delays tumor growth and exhibits synergistic effects with anti-PD1 therapy in various syngeneic tumor models. This combination enhances STING activity and promotes the infiltration and activation of CD8+ T cells within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings identify CDK12/13 as promising therapeutic targets for enhancing ICB efficacy, highlighting their potential to amplify STING-mediated anti-tumor immunity. This work provides a mechanistic framework for leveraging CDK12/13 antagonists in combination with ICB to improve clinical outcomes in cancer therapy. Overall design: Two CDK12-mutant and two CDK12 wildtype metastatic prostate cancer samples were subjected to spatial transcriptomics analysis to evaluate genes that were differently expressed in CDK12 mutant samples compared to the wildtype.