An Engineered Microbial Nanohybrid for Enhanced Ferroptosis Immunotherapy via Hypoxia-Responsive Hydrogen Sulfide Generation and Mitophagy Inhibition

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.