Self‐Propelled Bacteria‐Mediated In Situ Biosynthesis of MnS Nanoparticles for Remodeling Tumor Microenvironment to Amplify cGAS‐STING Pathway for Antitumor Immunity

Abstract cGAS‐STING pathway, an important innate immune signaling pathway, has attracted extensive attention in anti‐tumor immunotherapy research. However, the limited delivery ratio of STING agonists and lactate‐induced lactylation present significant challenges in advancing cGAS‐STING antitumor immune response. Herein, natural anaerobic sulfate‐reducing bacteria (SRB) are utilized as a biofactory to in situ biosynthesize MnS nanoparticles (MnS@SRB) for amplifying MnS‐activated cGAS‐STING anti‐tumor immune responses through continuous lactate depletion by SRB. After intravenous injection, MnS@SRB can actively migrate to tumor tissues via SRB‐mediated hypoxia targeting, further continually release H 2 S and Mn 2+ in the acidic tumor microenvironment. H 2 S stimulates mitochondrial dysfunction and induces mitochondrial DNA leakage, which is then recognized by cGAS to activate STING signaling pathway. Mn 2+ further augments STING‐mediated secretion of type I interferons and inflammatory factors. Importantly, MnS@SRB can effectively metabolize lactate in tumors, thereby alleviating cGAS lactylation for amplifying cGAS‐STING immune response and regulating macrophage phenotype to M1‐type, reducing the tumor‐infiltrating regulatory T cells and increasing CD8 + T cells level, further enhancing both adaptive and innate immunosurveillance. As a result, MnS@SRB effectively inhibite the tumors growth and metastasis. Therefore, MnS@SRB‐based delivery system enables efficient cGAS activator delivery and tumor immunosuppressive microenvironment remodeling, thereby opening a new avenue for synergistically enhanced STING activation.