Abstract LB389: R-loop formation triggers STING-mediated anti-tumor immunity following inactivation of a cyclin-dependent kinase

Abstract We previously identified that the inactivation of a cyclin-dependent kinase defines an immunogenic molecular subtype of prostate cancer, characterized by genomic instability and enhanced intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that inactivation of this cyclin-dependent kinase or suppression of its paralog activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced expression of kinase correlates with improved survival and treatment response. Mechanistically, depletion or targeted degradation of the kinase induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, degradation of the kinase 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 a cyclin-dependent kinase 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 antagonists of the kinase in combination with ICB to improve clinical outcomes in cancer therapy. Citation Format: Yi Bao, Yu Chang, Ke Ding, Arul M. Chinnaiyan. R-loop formation triggers STING-mediated anti-tumor immunity following inactivation of a cyclin-dependent kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB389.