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–MnO2) 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–MnO2 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 Mn2+, 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.
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