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‐x C 2 T y nanosheets to construct the atomically dispersed Pd‐C 3 single atom catalysts (SAC) with Pd content up to 2.5 wt% (Pd SA /Ti 3‐x C 2 T y ). Compared with Pd nanoparticle loaded Ti 3‐x C 2 T y , Pd SA /Ti 3‐x C 2 T 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 H 2 O 2 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.