Gallium‐Magnesium Layered Double Hydroxide for Elevated Tumor Immunotherapy Through Multi‐Network Synergistic Regulation

Immunotherapeutic efficacy is often limited by poor immunogenicity, immunosuppressive tumor microenvironment (TME), and cytoprotective mechanisms, leading to low immune activation. To this end, here, L-amino acid oxidase (LAAO) loaded gallium-magnesium layered double hydroxide (MG-LAAO) is prepared for significantly enhanced tumor immunotherapy through multi-network synergistic regulation. First, MG-LAAO induces tumor cell pyroptosis by initiating caspase-1/GSDMD and caspase-3/GSDME pathways, further triggering immunogenic cell death (ICD). Then the released Ga³⁺ induces mitochondrial iron overload, resulting in ferroptosis. In addition, MG-LAAO also hinders autophagy of tumor cells, and reshapes the immunosuppressive tumor microenvironment (TME) by neutralizing H⁺ and inhibiting lactic acid accumulation, thus destroying the cytoprotective mechanism and avoiding immune escape. Furthermore, this multi-network synergy further activates the cGAS-STING signaling pathway, generating powerful antitumor immunotherapy. This work highlights the critical role of synergies between autophagy block, pyroptosis, ferroptosis, and ICD in tumor immunotherapy, demonstrating the important role of this multi-network synergy in effectively overcoming immunosuppressive TME and enhancing immunogenicity. In particular, the mechanism of gallium-induced pyroptosis is revealed for the first time, providing theoretical support for the design of new materials for tumor immunotherapy in the future.