Single Atom Catalysts Remodel Tumor Microenvironment for Augmented Sonodynamic Immunotherapy.

Abstract

The immunosuppressive tumor microenvironment (TME) is a huge hurdle in immunotherapy. Sono-immunotherapy is a new treatment modality that can reverse immunosuppressive TME, but the sonodynamic effects are compromised by overexpressed glutathione (GSH) and hypoxia in the TME. Herein, this work reports a new sono-immunotherapy strategy using Pd^δ+ single atom catalysts to enhance positive sonodynamic responses to the immunosuppressive and sono-suppressive TME. To demonstrate this technique, this work employs rich and reductive Ti vacancies in Ti_3-xC₂T_y nanosheets to construct the atomically dispersed Pd-C₃ single atom catalysts (SAC) with Pd content up to 2.5 wt% (Pd_SA/Ti_3-xC₂T_y). Compared with Pd nanoparticle loaded Ti_3-xC₂T_y, Pd_SA/Ti_3-xC₂T_y single-atom enzyme showed augmented sonodynamic effects that are ascribed to SAC facilitated electron-hole separation, rapid depletion of overexpressed GSH by ultrasound (US) excited holes, and catalytic decomposition of endogenous H₂O₂ for relieving hypoxia. Importantly, the sono-immunotherapy strategy can boost abscopal antitumor immune responses by driving maturation of dendritic cells and polarization of tumor-associated macrophages into the antitumoral M1 phenotype. Bilateral tumor models demonstrate the complete eradication of localized tumors and enhance metastatic regression. Th strategy highlights the potential of single-atom catalysts for robust sono-immunotherapy by remodeling the tumor microenvironment.