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

Abstract 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 (H 2 O 2 ) to hydroxyl radicals (·OH) and oxygen (O 2 ). Moreover, FeCu‐DA exhibits superior glutathione‐oxidase (GSH‐OXD) activity, catalyzing GSH oxidation to generate H 2 O 2 , 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 H 2 O 2 . 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.