Single-Atom Nanozymes for High-Efficiency Cancer Immunotherapy by Targeting Tumor Microenvironment.

Tumor immunotherapy has emerged as a transformative strategy for cancer treatment. However, its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME), which restricts immune cells infiltration, suppresses effector cells activity, and promotes immune escape. Recent advances in catalytic nanomedicine have highlighted single-atom nanozymes (SAzymes) as a promising platform for overcoming these barriers. Owing to their atomic precision and tunable electronic structure, SAzymes exhibit highly efficient enzyme-like catalytic activities and enable precise regulation of the TME. Through catalytic therapy, SAzymes can alleviate hypoxia, regulate lactate accumulation, disrupt redox homeostasis, and reprogram immunosuppressive immune cells populations. Importantly, SAzyme-mediated catalytic therapy can induce immunogenic cell death (ICD), thereby enhancing antitumor immune responses. In addition, the well-defined atomic architecture of SAzymes provides a unique opportunity to establish quantitative structure-activity relationships (QSAR), enabling rational optimization of catalytic performance through modulation of their composition and coordination environment. This review systematically summarizes the mechanisms by which SAzymes remodel the TME and enhance cancer immunotherapy, discussing recent advances in atomic level design principles and multimodal synergistic therapy. Finally, current challenges and future perspectives, including machine learning-guided SAzymes design, biosafety and clinical translation, are discussed to guide the next generation of SAzyme-based catalytic immunotherapies.