Calcium peroxide loaded liposomes reprogram hypoxic and acidic tumor microenvironment to overcome lenvatinib resistance in hepatocellular carcinoma

Background Lenvatinib resistance severely limits the therapeutic efficacy in advanced hepatocellular carcinoma and is increasingly recognized as a systemic adaptive state driven by the hypoxic and acidic tumor microenvironment. However, effective strategies targeting these upstream constraints remain lacking. Methods Calcium peroxide–loaded liposomes (CaO 2 @Lipo) were synthesized to relieve hypoxia, neutralize acidity, and disrupt calcium homeostasis. Physicochemical properties and oxygen/pH-regulating capacity were characterized. Lenvatinib-resistant hepatocellular carcinoma models were established in vitro and in orthotopic tumors. The therapeutic efficacy and mechanisms of CaO 2 @Lipo, alone or combined with lenvatinib, were evaluated through cellular functional assays, histological analysis, immune profiling, and transcriptomic sequencing. Results CaO 2 @Lipo induced pronounced calcium overload and mitochondrial dysfunction, leading to marked cytotoxicity in resistant cells. In orthotopic resistant models, CaO 2 @Lipo significantly enhanced the antitumor efficacy of lenvatinib, resulting in robust tumor suppression and prolonged survival without evident systemic toxicity. Mechanistically, combined treatment markedly downregulated the hypoxia associated resistance signaling axis involving HIF-1α, VEGF, CA9 and ABCB1. Moreover, CaO 2 @Lipo triggered immunogenic cell death, enhanced dendritic cell infiltration, increased CD8 + T cell recruitment and shifted systemic cytokine profiles toward a proinflammatory phenotype. Conclusion CaO 2 @Lipo reprograms the hypoxic and acidic tumor microenvironment, dismantles resistance sustaining networks and restores lenvatinib responsiveness in hepatocellular carcinoma.