A metal anion strategy to induce pyroptosis combined with STING activation to synergistically amplify anti-tumor immunity

Growing evidence has demonstrated the positive role of bioactive metal ions in enhancing pyroptosismediated cancer immunotherapy. However, further amplification of the sustained immune response remains challenging. Herein, by selecting from typical metal anions, we confirmed the significant cytotoxicity and pyroptosis induction potency of vanadate anions, owing to the inhibition of ATPases and disruption of intracellular ion homeostasis. Then, PEGylated bimetallic manganese vanadate nanoparticles (MnVOx) were synthesized for stimulator of interferon genes (STING) pathway-boosted pyroptosis therapy. The vanadate produced from MnVOx degradation inhibited membrane ATPases and induced potassium efflux and calcium overload, resulting in inflammasome activation, mitochondrial damage, and endoplasmic reticulum stress, as well as subsequent robust pyroptotic cell death. The released manganese ions stimulated STING pathway through dendritic cells maturation and type I interferon secretion. This dual strategy triggered strong anti-tumor immunity and promoted immune cell infiltration into the tumor, which further defeated distant tumors in combination with immune checkpoint blockade (ICB) therapy. Moreover, by dispersing MnVOx with lipiodol for interventional transarterial embolization (TAE) therapy, an enhanced therapeutic efficacy was achieved in orthotopic rabbit liver cancer compared to that of lipiodol alone. Our work highlights the biological effect of metal anions in inducing pyroptosis, as well as the synergistic immunotherapy involving pyroptosis induction and STING activation.