Dual-Targeted Microspheres Reshape the Metabolic-immune Microenvironment and Reverse Multiple Dilemmas Post-embolization in Hepatocellular Carcinoma

Transarterial embolization (TAE) efficacy in hepatocellular carcinoma (HCC) is limited by post-embolization hypoxia-driven angiogenesis and metabolic reprogramming. To address these challenges, pH-responsive gelatin microspheres encapsulating zinc sulfide (ZnS) nanoparticles (ZnS@GMs) were developed for the dual delivery of hydrogen sulfide (H2S) gas and Zn2+ ions. ZnS@GMs significantly suppressed tumor growth through suppression of the HIF-1α/VEGF axis and glycolytic metabolism, alongside promoting vascular normalization and immune activation. Mechanistically, H2S disrupted mitochondrial respiration, increasing oxygen levels and destabilizing HIF-1α, whereas Zn2+ inhibited hexokinase and lactate dehydrogenase, depleting ATP and biosynthetic intermediates. Furthermore, ZnS@GMs induced immunogenic cell death, which triggered dendritic cell maturation, cytotoxic T-cell infiltration, and macrophage repolarization, thereby enhancing the efficacy of anti-PD-1 therapy. In a rabbit orthotopic liver tumor model, intra-arterial infusion of ZnS@GMs confirmed potent antitumor effects and excellent embolic performance. This work establishes ZnS@GMs as a multifunctional platform to overcome TAE resistance in HCC.