Potentiating the Systemic Immunity by Bacteria-Delivered Sting Activation in a Tumor Microenvironment

Stimulator of interferon genes (STING) connects the innate immunity to potent adaptive immunity via multiple pathways, which play a critical role in cancer treatment. Clinical application of STING agonists is mainly restrained due to the metabolic instability caused by intrinsic cyclic dinucleotide ligands. Previously, an orally available non-nucleotide human STING agonist, MSA-2 is presented, and to further improve its therapeutic efficacy, this work leverages the nonpathogenic Escherichia coli Nissle 1917 for tumor-targeted delivery of the STING agonist by coating biocompatible polydopamine on the bacterial surface, termed as PDMN. The engineered bacterial delivery platform holds potential in elevating levels of type I interferon (IFN) along with proinflammatory cytokines and inducing maturation on dendritic cells. Intravenous administration of PDMN with laser irradiation to the tumor region promotes IFN-& beta; expression in a tumor microenvironment and mounts both the innate and adaptive immune responses, leading to profound regressions of established melanoma and hepatocellular carcinoma in mice. By synergized with anti-PD-1 therapy, a substantial long-lived protective immunity is generated, capable of preventing distant tumor metastases. Hence, this study identifies a STING-amplified biotherapy to shape the cell-mediated antitumor immunity, serving as a potential personalized cancer vaccine with enhanced biosafety and immune activation profile for diverse applications. This formulated PDMN constitutes a biological product that preferentially colonizes and penetrates into tumor regions, as well as activates STING on dendritic cells, leading to the differentiation of cell-mediated immunity and secretion of proinflammatory cytokines. This STING-amplified biotherapy efficiently restrains the growth of local and distant tumors, and shows synergy when combined with PD-1 blockade to elicit a long-lived immunity.image