An Engineered Microbial Nanohybrid for Enhanced Ferroptosis Immunotherapy via Hypoxia-Responsive Hydrogen Sulfide...

Ferroptosis immunotherapy holds promise but suffers from insufficient activation of antitumor immunity. Here, we developed an engineered microbial nanohybrid for enhanced ferroptosis immunotherapy via hypoxia-triggered hydrogen sulfide (H₂S) generation and activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. The engineered microbial nanohybrid could locally produce H₂S in the hypoxic tumor microenvironment, damaging mitochondria and inhibiting catalase. Concurrently, surface-conjugated ferrocene potently catalyzed the Fenton reaction to convert hydrogen peroxide into hydroxyl radicals, leading to ferroptosis and the release of mitochondrial DNA (mtDNA). Furthermore, the loaded Mdivi-1 acts as a critical molecular brake on cellular self-repair, overcoming the mitophagic clearance of damaged mitochondria. This intervention locks in mitochondrial damage, thereby promoting the sustained accumulation of cytosolic mtDNA and potently activating the cGAS-STING pathway. The enhanced ferroptosis immunotherapy by the engineered microbial nanohybrid was confirmed in a 4T1 murine mammary carcinoma model. Therefore, this study provides a promising strategy for precise and potent antitumor immunotherapy.