Manganese-enriched photonic/catalytic nanomedicine augments synergistic anti-TNBC photothermal/nanocatalytic/immuno-therapy via activating cGAS-STING pathway.

Abstract

As the clinical efficacy of immunotherapy for triple-negative breast cancer (TNBC) remains limited, exploring new immunotherapy approaches is still indispensable. Mn²⁺ has been proven as a cGAS-STING agonist to remarkably enhance antitumor immunity. Here, we report a combined tumor-therapeutic strategy based on Prussian blue (PB)-mediated photothermal therapy with Mn²⁺-augmented immunotherapy by synergistically activating the cGAS-STING pathway. Mn-enriched photonic nanomedicine (MnPB-MnO_x) were constructed by integrating MnO_x onto the surface of Mn-doped PB nanoparticles. All components of MnPB-MnO_x are biocompatible and biodegradable, wherein sufficient Mn are endowed through rational nanostructure design, conferring easier cGAS-STING activation. Additionally, tumor hyperthermia strengthened by MnPB under near-infrared light radiation, synergistic with the generation of reactive oxygen species catalyzed by MnO_x, double hits cancer cells to release abundant tumor-associated antigens for further promoting immune response stimulation. The local anti-TNBC efficacy of photothermal/immuno-therapy has been proven effective in subcutaneous 4T1-bearing mice. Especially, it has been systematically demonstrated in bilateral orthotopic 4T1-bearing mice that the as-proposed treatment could successfully activate innate and adaptive immunity, and local therapy could engender systemic responses to suppress the distant tumors. Collectively, this work represents a proof-of-concept for a non-invasive Mn-based tumor-immunotherapeutic modality, providing a paradigm for the immunotherapy of metastatic-prone tumors.