Engineered Bacillus Calmette-Guérin Mediated Immunotherapy of Triple-Negative Breast Cancer.

Live bacterial therapy has shown promise in inducing antitumor immunity, but its efficacy is often limited by the immunosuppressive tumor microenvironment (TME) and insufficient tumor-specific T cell activation. In this study, core-shell Au@ZnMnS nanoparticles (AZMS) were synthesized and covalently conjugated to Bacillus Calmette-Guérin (BCG) to generate the engineered bacterium AZMB, which was subsequently encapsulated within a hyaluronic acid-based matrix to fabricate the functional implant AZMB-IM. Upon percutaneous administration via a puncture needle, BCG acts as a potent immune initiator, significantly enhancing the recruitment of M1-type macrophages and natural killer cells to the tumor site, and also induced the maturation of dendritic cells. Concurrently, AZMB dissociates in the TME, releasing Zn and Mn ions. Zn disrupts the mitochondrial membrane potential, triggering a reactive oxygen species (ROS) storm and inducing immunogenic cell death (ICD). Meanwhile, Mn amplifies the ROS effect via a Fenton-like reaction and activates the cGAS-STING signaling pathway, which in turn drives robust T cell-mediated antitumor immunity. Collectively, through synergistic activation of innate immunity and ICD-driven adaptive immune responses, AZMB-IM remodels the TME and enhances antitumor immunity, highlighting its significant potential for clinical translation in the treatment of advanced and metastatic solid tumors.