A Synergistic Dual-Atom Sites Nanozyme Augments Immunogenic Cell Death for Efficient Immunotherapy

Inducing immunogenic cell death (ICD) is a promising approach to elicit enduring antitumor immune responses. Hence, extensive efforts are being made to develop ICD inducers. Herein, a cascaded dual-atom nanozyme with Fe and Cu sites (FeCu-DA) as an efficient ICD inducer is presented. The Fe and Cu dual-atom sites synergistically enhance peroxidase (POD) and catalase activities, effectively converting intratumoral hydrogen peroxide (H₂O₂) to hydroxyl radicals (·OH) and oxygen (O₂). Moreover, FeCu-DA exhibits superior glutathione-oxidase (GSH-OXD) activity, catalyzing GSH oxidation to generate H₂O₂, enabling cascaded catalysis for sustainable ∙OH generation and reducing reactive oxygen species (ROS) resistance by consuming GSH. Steady–state kinetic analysis and density functional theory calculations indicate that FeCu-DA exhibits a higher catalytic rate and efficiency than Fe single-atom nanozymes (Fe-SA) because of its stronger interactions with H₂O₂. Its POD activity is 948.05 U mg⁻¹, which is 2.8-fold greater than that of Fe-SA. Furthermore, FeCu-DA exhibits impressive photothermal effects and photothermal-enhanced cascaded catalysis kinetics for ROS generation, thereby inducing potent ICD. Combined with anti-PD-L1 antibody (αPD-L1) blockade, FeCu-DA shows synergistic enhancement in treatment under near-infrared irradiation. This study provides insights for designing efficient dual-atom nanozymes and demonstrates their potential in ICD-induced cancer immunotherapy.