Coordination-environment engineering of a sulfur-modified copper single-atom nanozyme enables electronic structure modulation toward systemic antineoplastic therapy.

Precise manipulation of atomic coordination environments in single-atom nanozymes offers a powerful strategy to regulate catalytic activity, yet achieving simultaneous enhancement of active-site density and intrinsic catalytic efficiency remains challenging. Here, we develop a sulfur-modulated copper single-atom nanozyme (CuN3S) featuring an asymmetric N3S coordination configuration, which differs fundamentally from conventional CuN4 active sites and previously reported S-doped Cu catalysts. The introduction of sulfur not only increases the copper loading density by stabilizing additional atomic Cu centers but also induces distinct electronic redistribution around the Cu active site. Density functional theory calculations reveal that the N3S coordination environment shifts the Cu d-band center toward the Fermi level, strengthens H2O2 adsorption, facilitates interfacial charge transfer, and optimizes Cu-O intermediate formation, thereby promoting superior peroxidase-like catalytic activity. Compared with the CuN4 counterpart, CuN3S exhibits enhanced reactive oxygen species generation under tumor microenvironment conditions, effectively disrupting redox homeostasis and inducing apoptosis, ferroptosis, and immunogenic cell death. In bilateral and metastatic 4T1 tumor models, CuN3S further activates systemic antitumor immunity, resulting in efficient inhibition of both primary and distant tumors. This work establishes coordination-environment engineering of single-atom nanozymes as an effective approach to simultaneously optimize atomic utilization, electronic structure, and catalytic-immune therapeutic outcomes, providing new insights into the rational design of advanced nanozyme-based cancer therapies.