Multi‐Metallic Nanosheets Reshaping Immunosuppressive Tumor Microenvironment through Augmenting cGAS‐STING Innate Activation and Adaptive Immune Responses for Cancer Immunotherapy

Abstract The highly immunosuppressive tumor microenvironment (TME) restricts the efficient activation of immune responses. To restore the surveillance of the immune system for robust activation, vast efforts are devoted to normalizing the TME. Here, a manganese‐doped layered double hydroxide (Mn‐LDH) is developed for potent anti‐tumor immunity by reversing TME. Mn‐LDH is synthesized via a one‐step hydrothermal method. In addition to the inherent proton neutralization capacity of LDH, the introduction of manganese oxide endows LDH with an additional ability to produce oxygen. Mn‐LDH effectively releases Mn²⁺ and Mg²⁺ upon exposure to TME with high levels of H⁺ and H₂O₂, which activates synthase‐stimulator of interferon genes pathway and maintains the cytotoxicity of CD8⁺ T cells respectively, achieving a cascade‐like role in innate and adaptive immunity. The locally administered Mn‐LDH facilitated a “hot” network consisting of mature dendritic cells, M1‐phenotype macrophages, as well as cytotoxic and helper T cells, significantly inhibiting the growth of primary and distal tumors. Moreover, the photothermal conversion capacity of Mn‐LDH sparks more robust therapeutic effects in large established tumor models with a single administration and irradiation. Overall, this study guides the rational design of TME‐modulating immunotherapeutics for robust immune activation, providing a clinical candidate for next‐generation cancer immunotherapy.