A radionuclide-labeled nanomedicine for STING pathway activation- and oxygenation-augmented orthotopic cancer radioisotope-immunotherapy

Current internal radioisotope therapy (RIT) struggles to achieve desirable treatment outcomes in solid tumors due to inadequate tumor-targeted delivery of radionuclides, and the hypoxic and immunosuppressive tumor microenvironment (TME). In this study, we rationally design and fabricate a radionuclide-labeled nanomedicine in which a tumor-targeting metal-phenolic network (MPN) is coated on the surface of 32 P-labeled biomineralized calcium phosphate (C-Ca 32 P) nanoparticles to realize targeted delivery of radionuclides and ABZI (a stimulator of interferon genes (STING) agonist). After internalization by tumor cells, such nanomedicine could alleviate hypoxia by oxygenation. Meanwhile, the pH-responsive decomposition of this nanomedicine triggers the liberation of radioactive 32 P, Mn 2+ and ABZI from acidic lysosomes, wherein ABZI and Mn 2+ synergistically potentiate STING signaling. Notably, the activation of STING pathway and in situ oxygenation sensitize tumor cells to 32 P-midiated internal radiation and arouse a type I interferons (IFNs)-related adaptive immune response, achieving obvious synergistic effect in eradicating orthotopic breast tumors. After combination with checkpoint blockade therapy, this nanomedicine could lead to amplified therapeutic effect and inhibition of distant tumor metastases. This study presents a promising strategy for internal radiation sensitization and immune activation, holding significant potential for enhanced radioisotope-immunotherapy.