Rational Design of Single‐Atom Nanozymes for Combination Cancer Immunotherapy

Abstract Remodeling of the tumor immune microenvironment and enhancement of antitumor immune responses are necessary to overcome immunotherapy resistance in tumors. However, tumor heterogeneity and complexity of immune evasion mechanisms pose significant therapeutic challenges. Nanozymes exhibit enzyme‐like characteristics and unique nanomaterial properties, showing potential for tumor therapy. However, design of effective nanozymes remains complex, inefficient, and functionally limited. Therefore, in this study, a novel strategy combining rationally designed single‐atom nanozymes (SAzymes) with immune checkpoint blockade (ICB) therapy is established. Molybdenum SAzymes supported on graphitic carbon nitride (Mo SAs) are constructed using 25 transition metal candidates from the 4th to 6th periods based on high‐throughput calculations and optimal piezoelectric‐enhanced multienzyme‐like activities. Upon activation by ultrasound, Mo SAs exerted potent therapeutic effects against ICB‐resistant tumors and remodeled the tumor immune microenvironment by inducing tumor immunogenic cell death, alleviating tumor hypoxia, and modulating chemokine expression in tumors. Combination of Mo SAs with anti‐programmed death protein‐1 antibodies further enhanced their antitumor efficacy, highlighting their potential to treat ICB‐resistant tumors.