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

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.