AgBiS2 and Mn2+ mediated live bacteria therapy for photothermal and immunotherapy against triple-negative breast cancer

As a non-invasive antitumor therapy, photothermal therapy (PTT) faces significant hurdles in clinical translation, due to the limited tissue penetration of photothermal agents and the limited efficacy against distant metastases. Although engineered bacteria hold promise for addressing these challenges owing to their intrinsic tumor-targeting capability and immunogenicity, their intravenous administration is often hindered by limitations such as premature drug shedding and potential systemic toxicity. To overcome these challenges, we designed an in situ implantable, multifunctional local delivery system AEM IMP (an implant containing engineered bacteria ABSE and manganese ions). By co-loading Mn2+ and ABSE (AgBiS2 nanoparticle-modified E. coli), this system achieves localized delivery of engineered bacteria to tumor sites, synergistically enhancing photothermal-immunotherapy. After implantation, the engineered bacteria colonize hypoxic tumor regions, thereby facilitating deep penetration of AgBiS2 into tumor tissues. Under near-infrared irradiation, the photothermal effect mediated by ABSE effectively induced immunogenic cell death in tumor cells, promoting the maturation of dendritic cells (DCs) and facilitating the recruitment of cytotoxic T cells. Simultaneously, the photothermal effect serves to eradicate E. coli bacteria, resulting in the release of immune-stimulating adjuvant elements that enhance the polarization of tumor-associated macrophages towards an M1-like phenotype. Additionally, the liberated Mn2+ serve to potently activate the cGAS-STING signaling pathway, remodeling the immunosuppressive tumor microenvironment and initiating systemic antitumor immune responses. In summary, the AEM IMP system developed in this study achieves effective local delivery of engineered bacteria while synergistically enhancing photothermal immunotherapy, offering a novel combinatorial strategy with translational potential for the clinical application of PTT.