Silver Molybdate Nanoparticles for Enhanced Tumor Immunotherapy through Pyroptosis Conversion and Ferroptosis Induction

Pyroptosis holds great potential in tumor therapy due to its strong immunogenicity. Several strategies, including ion interference therapy (IIT), are developed to induce pyroptosis. However, the mechanism by which metal oxoanions induced pyroptosis remained unclear. It was reported that MoO₄ ^2- ions could stimulate immune responses, but their pyroptosis-inducing mechanisms were not fully understood. Herein, we synthesized uniform and dispersed silver molybdate (Ag₂MoO₄) nanoparticles (AMO) via a solvothermal method. AMO responded to H₂O₂ and glutathione (GSH) stimuli, releasing Ag⁺ and MoO₄ ^2- ions, generating reactive oxygen species (ROS), and depleting GSH, thereby inducing ferroptosis and pyroptosis. The MoO₄ ^2- also inhibited cell migration and upregulated GSDME expression, converting apoptosis into caspase-3/GSDME-mediated pyroptosis. Additionally, DNA damage and ROS activated the cGAS-STING pathway, enhancing innate immunity. In vivo experiments demonstrated that the combination of AMO and the immune checkpoint inhibitor αPD-1 significantly inhibited tumor growth. This combination promoted dendritic cells (DCs) maturation, increased effector T cell numbers, induced M1 macrophage polarization, and alleviated immunosuppression. This study contributed to a deeper understanding of metal oxoanion-mediated pyroptosis, supporting its potential application in cancer immunotherapy.