Regulating HIF-2α stabilization with an intelligent switchable nanoplatform for tumor immunity reprogramming and enhanced therapy.

Chronic hypoxia is a critical barrier to the effective treatment of solid tumors, including hepatocellular carcinoma (HCC), as it not only restricts the oxygen supply required for sonodynamic therapy (SDT) but also upregulates hypoxia-inducible factor-2α (HIF-2α), thereby accelerating tumor progression, inducing abnormal angiogenesis, suppressing antitumor immune responses, and diminishing the efficacy of targeted therapies. Here, we developed an intelligent switchable organic-inorganic hybrid nanoplatform (VitK3/P-Ce6@H-MnO) that integrates oxygen self-supply, reactive oxygen species (ROS) storm induction, and immune microenvironment reprogramming. The acidic tumor microenvironment serves as an "endogenous switch," triggering the decomposition of H-MnO to release oxygen and Vitamin K3, thereby alleviating chronic hypoxia, facilitating HIF-2α degradation, and providing oxygen support for Ce6-mediated SDT. Upon ultrasound exposure as an "exogenous switch," activated Ce6, together with Vitamin K3 and Mn, induces a robust ROS storm, resulting in mitochondrial dysfunction and immunogenic cell death (ICD), while effectively reprogramming the chronic hypoxia-HIF-2α-driven immunosuppressive tumor microenvironment. Furthermore, in vivo studies demonstrated that Lenvatinib therapy, when combined with the nanoplatform, further suppressed chronic hypoxia-HIF-2α-driven abnormal angiogenesis, enhanced CD8 T-cell infiltration, and boosted antitumor immune responses, ultimately achieving a potent synergistic therapeutic effect and promoting the conversion of "cold tumors" into "hot tumors." This study provides strong experimental evidence that nanoplatform-mediated immune microenvironment reprogramming represents a precisely controllable and highly effective therapeutic strategy for solid tumors, with promising translational potential in hepatocellular carcinoma.