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.

肿瘤的低免疫原性，加上肿瘤血管系统的异常和功能障碍，阻碍了效应T细胞的浸润和功能，抑制了免疫治疗的疗效。在此，我们开发了一种有缺陷的铜基金属有机框架单位点纳米酶（F@D-CHTP SN），其共载MSA-2（干扰素基因[STING]激动剂的刺激剂）和呋喹替尼（血管内皮生长因子）受体[VEGFR]抑制剂）。共轭有机配体和高度暴露的不饱和Cu-O ₂单原子位点赋予F@D-CHTP SN优异的活性氧生成活性，可以破坏细胞氧化还原平衡，损害线粒体功能，最终诱导铜死亡和铁死亡。增强肿瘤免疫原性。同时，瘤内STING激活和VEGFR阻断协同促进肿瘤血管正常化，进一步重塑免疫抑制微环境，增强T细胞浸润，实现有效的肿瘤抑制。我们的工作证明了通过将铜死亡和铁死亡与 STING 激活和肿瘤脉管系统正常化相结合来启动级联增强免疫的可行性和显着的协同效应。