Manganese molybdate nanodots with dual amplification of STING activation for “cycle” treatment of metalloimmunotherapy

Certain types of cationic metal ions, such as Mn2+ are able to activate immune functions via the stimulator of interferon genes (STING) pathway, showing potential applications in eliciting antitumor immunity. How anionic ions interact with immune cells remains largely unknown. Herein, selecting from a range of cationic and anionic ions, we were excited to discover that MoO42− could act as a cGAS-STING agonist and further confirmed the capability of Mn2+ to activate the cGAS-STING pathway. Inspired by such findings, we synthesized manganese molybdate nanoparticles with polyethylene glycol modification (MMP NDs) for cancer metalloimmunotherapy. Meanwhile, MMP NDs could consume glutathione (GSH) over-expressed in tumors and induce ferroptosis owing to high-valence Mo and Mn to elicit tumor-specific immune responses, which was further amplified by MMP-triggered the cGAS-STING activation. In turn, activated CD8+ T cells to secrete high levels of interferon γ (IFN-γ) and reduced GPX4 expression in tumor cells to trigger ferroptosis-specific lipid peroxidation, which constituted a "cycle" of therapy. As a result, the metalloimmunotherapy with systemic administration of MMP NDs offered a remarkable tumor inhibition effect for a variety of tumor models. Our work for the first time discovered the ability of anionic metal ions to activate the immune system and rationally designed bimetallic oxide nanostructures as a multifunctional therapeutic nanoplatform for tumor immunotherapy.