Targeting DNA repair with a Pt(IV) prodrug nanoparticle potentiates chemo-immunotherapy for nasopharyngeal carcinoma through cGAS-STING activation.

Cisplatin-based chemotherapy combined with immunotherapy is the standard first-line treatment for advanced nasopharyngeal carcinoma (NPC), but its efficacy is limited by off-target toxicity, platinum resistance, and the immunosuppressive tumor microenvironment (TME). Herein, we report NP2, a reactive oxygen species (ROS)-sensitive nanoparticle co-loaded with a platinum (IV) prodrug (CisPt-IV) and a CDK1 inhibitor (RO-3306), for targeted delivery to NPC through surface-functionalization with RGD peptide. Following intravenous administration, NP2 homes to NPC tissues overexpressing integrin receptors, where elevated ROS trigger NP2 degradation and subsequent drug release. RO-3306 blocks CDK1-driven DNA repair and prevents CDK1-mediated cGAS phosphorylation, amplifying cisplatin-induced DNA damage and enhancing cGAS activity. Such dual action potently activates the cGAS-STING signaling pathway and promotes anti-tumor immunity. In murine NPC models, NP2 effectively suppresses tumor progression and reshapes the TME, converting "cold" tumors into "hot" tumors and establishing durable immune memory. By integrating precise targeting, DNA-repair inhibition, and immune activation, NP2 offers a promising strategy to overcome cisplatin resistance and enhance the therapeutic index of combined chemo-immunotherapy in NPC.