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

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.