Immunosuppressive Microenvironment Reprogramming by Synergistic Sonodynamic Therapy of Phthalocyanine‐MOF Hybrids for Hepatocellular Carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) remains a critical global health challenge with limited treatment efficacy hindered by therapy resistance and hypoxia‐induced immune suppression. Tumor heterogeneity and low immune cell reactivity often lead to tolerance and failure of immunotherapy. Sonodynamic therapy (SDT) has emerged as a promising precision treatment with non‐invasive characteristics and localized tumor targeting, offering potential for remodeling the immunosuppressive tumor microenvironment. This study introduces a novel phthalocyanine‐metal‐organic framework hybrid (Pc@Zr‐MOF) designed for SDT and immune regulation in HCC. By enhancing the efficiency of ultrasonic conversion and synergy, Pc@Zr‐MOF induces robust tumor cell apoptosis while simultaneously reshaping the immune landscape. Single‐cell RNA sequencing reveals its ability to promote M1 macrophage polarization and increase cytotoxic T cell infiltration with tumor‐associated macrophages. These effects highlight its dual mechanism of direct tumor eradication and immune microenvironment remodeling. Moreover, Pc@Zr‐MOF demonstrates admirable biocompatibility and minimal off‐target toxicity, which underscores its clinical translational potential. By synergizing SDT with immune reprogramming, this approach addresses hypoxia‐driven resistance and establishes durable anti‐tumor immunity. This study aims to change the current situation of advanced HCC treatment characterized by reconfiguration of tumor cell subpopulations and immunosuppression, thereby bringing a new paradigm to the precise treatment of HCC.