Bridging DNA damage and cGAS-STING activation: Platinum (IV) prodrugs as single-molecule chemo-immunotherapeutics.

Abstract

Cisplatin-based chemotherapy remains a cornerstone in cancer treatment, yet its clinical utility is often hampered by severe systemic toxicity and the cold immune microenvironment of many tumors. To address these challenges, we leveraged the kinetically inert nature and structural versatility of the Platinum (IV) [Pt (IV)] scaffold to design a series of dual-action prodrugs, RS-01-04, by axially conjugating the STING agonist CMA onto a Pt (IV) center. This Pt (IV) platform ensures enhanced stability in systemic circulation while enabling tumor-specific activation through responsive reduction. Among the derivatives, RS-04 exhibited superior lipophilicity and significantly increased intracellular platinum accumulation compared to cisplatin. Under simulated reductive conditions, RS-04 underwent rapid intracellular conversion to release active cisplatin and CMA, thereby triggering a robust synergistic effect. Detailed mechanistic studies demonstrated that RS-04 not only induced profound DNA damage (as evidenced by γ-H2AX foci and comet assays) and mitochondrial-mediated apoptosis via ROS elevation, but also successfully bypassed the limitations of "cold" tumors by activating the cGAS-STING-IFN-β signaling axis. In vivo evaluations confirmed that RS-04 achieved potent tumor growth inhibition with markedly reduced systemic toxicity compared to the physical combination of its parent drugs. These results highlight the clinical potential of utilizing the Pt (IV) framework as a sophisticated delivery vehicle to synchronize DNA damage with innate immune activation for superior cancer therapy.