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. • Novel dual-targeting strategy: We are the first to propose and validate a dual mechanism in NPC that simultaneously sensitizes chemotherapy and reverses immune suppression by targeting CDK1. Through bioinformatic analysis, we reveal that high CDK1 expression correlates positively with DNA damage repair and negatively with cGAS-STING signaling. This discovery establishes CDK1 as a novel node to achieve targeting and immune activation. • Precision-designed nanoparticle system: We constructed NP2 as a ROS-responsive, RGD-functionalized nanocarrier capable of high-efficiency, controlled drug release. By combining αvβ3-integrin-mediated active targeting with ROS-triggered drug release, this system addresses common limitations of nanocarriers with insufficient targeting and uncontrolled release. • Synergistic immune activation strategy: By co-activating the cGAS-STING pathway, NP2 effectively converts “cold” NPC tumors into “hot” tumors. CisPt-IV initiates cGAS-STING activation through DNA damage, while RO-3306 amplifies this signal by inhibiting CDK1-mediated DNA repair and dephosphorylating cGAS inhibition. This “initiate + amplify” strategy achieves sustained STING activation, resulting in superior immune remodeling and durable tumor regression.
Gao et al. (Wed,) studied this question.