Nano‐Engineered Magnesium Implants for Magnetothermal Enhanced Pyroptosis to Boost Immunotherapy

Abstract Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer‐related death because the immunosuppressive tumor microenvironment (TME) limits its therapeutic efficacy. Gasdermin (GSDM)‐mediated pyroptosis is a new programmed cell death that can boost antitumor immune responses. However, inducing efficient pyroptosis to reverse the immunosuppressive TME is challenging. Herein, layered double hydroxide‐coated magnesium (Zn‐LDH@Mg) implants are designed and constructed as alternating magnetic field (AMF)‐activated pyroptosis inducers to induce highly effective pyroptosis in cancer cells. The powerful eddy‐thermal effects of Zn‐LDH@Mg implants markedly amplify pyroptosis in malignant cells through the Caspase‐1/GSDMD‐dependent canonical pathway. Moreover, Mg²⁺ and pyroptosis synergistically activate T cells (especially CD8⁺ T cells) and enhance the infiltration of immune‐supportive cells. This innovative strategy not only significantly suppresses the proliferation of the primary tumor but also stimulates the immune response to further enhance the efficacy of immune checkpoint inhibitors and impede the progression of distant tumors. This work not only emphasizes the importance of surface engineering strategies for the preparation of novel pyroptosis inducers but also highlights the effectiveness of the strategy in reversing the immunosuppressive TME to enhance immunotherapy, providing a new approach for the rational design of bioactive materials to increase the efficacy of immunotherapy.