Bimetallic Ca/Zn Nanoagonist Remould the Immunosuppressive Hepatocellular Carcinoma Microenvironment Following Incomplete Microwave Ablation via Pyroptosis and the STING Signaling Pathway

Abstract During the treatment of solid tumors, local therapeutic approaches carry the risk of incomplete radical cure, which may lead to rapid tumor growth. Incomplete microwave ablation (iMWA) can induce tumors to exhibit highly invasive and uncontrollable growth, which is related to the immunosuppressive microenvironment. A multifunctional bimetallic Ca/Zn nanoagonist (PZH/Zn@CaNA) with a biomimetic liposome‐modified surface to tumor tissues after iMWA is developed. In response to the acidic tumor microenvironment, the released traditional Chinese medicine preparation Pien Tze Huang (PZH) reduced protein expressions of the JAK2‐STAT3 signaling pathway, thereby slowing down the proliferation and growth of hepatocellular carcinoma (HCC). Furthermore, the bimetallic ions Ca ² ⁺ and Zn ² ⁺ can cascade to enhance the killing effect of oxidative stress, generating substantial amounts of reactive oxygen species. This process induces pyroptosis and releases significant quantities of damage associated molecular patterns, thereby triggering immune activation mechanisms related to the STING pathway that reshape the immunosuppressive HCC microenvironment resulting from iMWA. This strategy markedly differs from previous chemoimmunotherapies, which not only effectively addressed the problem of conventional drugs showing heterogeneous distribution in tumor regions, but also verified the critical role played by PZH/Zn@CaNA in inhibiting iMWA‐induced rapid tumor growth, regulating oxidative stress and remodeling the immunosuppressive tumor microenvironment.