Ultrathin Clay Nanoparticles‐Mediated Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy

Abstract Ferroptosis‐triggered immunogenic cell death (ICD) is widely adopted to potentiate the body's antitumor immunity by catalyzing the production of toxic reactive oxygen species (ROS). However, the efficacy of ferroptosis and immunotherapy is greatly restricted by intracellular abundant glutathione (GSH) and immunosuppressive tumor microenvironment (TME). Herein, a facile bottom‐up method for solvent‐free synthesis of ultrathin manganese (Mn)‐based layered double hydroxide nanosheets with high loading efficiency for pro‐inflammatory cytokine interferon (IFNγ) (IFNγ/uMn‐LDHs) is proposed to mutually reinforce the ferroptosis and systemic immunity. The introduction of manganese ions significantly contributes to GSH depletion and hydroxyl radical generation, which can be further enhanced by IFNγ delivery‐induced SLC7A11 downregulation. The ICD effect after cell ferroptosis cooperates with the intrinsic immunomodulatory property of IFNγ/uMn‐LDHs to facilitate the maturation of dendritic cells (DCs) and the priming of T cells. IFNγ secretion from activated CD8⁺ T cells in turn involves cascade immunogenic ferroptosis, thus constructing a closed‐loop therapy. Remarkably, a potent abscopal effect is observed in the growth inhibition of both primary and distant tumors. Overall, the ultrathin Mn‐based clay nanoplatform provides a simple approach for mutual regulation between ferroptosis and antitumor immune response, overcoming the obstacles of current cancer immunotherapy.