Single-site nanozyme with exposed unsaturated Cu-O2 sites for tumor therapy by coordinating innate immunity and vasculature normalization

The low immunogenicity of tumors, coupled with abnormal and dysfunctional tumor vasculature, hinders the infiltration and function of effector T cells and suppresses the efficacy of immunotherapy. Herein, we developed a defective-copper-based metal-organic framework single-site nanozyme (F@D-CHTP SN) with co-loaded MSA-2 (stimulator of interferon genes [STING] agonist) and fruquintinib (vascular endothelial growth factor receptor [VEGFR] inhibitor). The conjugated organic ligands and highly exposed unsaturated Cu-O₂ single-atom sites endow F@D-CHTP SN with excellent reactive oxygen species generation activity, which can disrupt the cellular redox balance, impair mitochondrial function, and ultimately induce cuproptosis and ferroptosis, enhancing tumor immunogenicity. Meanwhile, intratumoral STING activation and VEGFR blockade synergistically promote tumor vasculature normalization, further reshaping the immunosuppressive microenvironment and enhancing T cell infiltration to achieve effective tumor suppression. Our work demonstrates the feasibility and significant synergistic effects of initiating cascade-enhancing immunity by combining cuproptosis and ferroptosis with STING activation and tumor vasculature normalization.