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

Abstract 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‐β 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.