Li Bin, Hu Houyang, Li Songyan, Wang Xuechun, Ma Zilin, Zhao Wen, Song Yunxuan, Jiao Jianwei, Xu Fenglei, Duan Xiuying, Zhang Guiqiang
Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
ACS Appl Mater Interfaces. 2025 Sep 17;17(37):51659-51670. doi: 10.1021/acsami.5c10711. Epub 2025 Sep 4.
Abnormal glycolysis and glutamine metabolism not only sustain tumor growth but also reprogram the tumor microenvironment (TME). However, due to compensatory mechanisms and low tumor immunogenicity, targeting a single metabolic pathway is often insufficient for effective cancer therapy. We here developed dual-starvation therapeutic metal-phenolic nanocapsules (CG@Cap) by encapsulating a glutamine metabolism inhibitor with a zeolitic imidazolate framework-8 and adsorbing glucose oxidase on the surface, followed by coordination-driven assembly with tannic acid and copper ions. After preferential accumulation at tumor sites and internalization by tumor cells, the nanocapsules release their cargo, simultaneously suppressing glycolysis and glutamine metabolism. This dual inhibition disrupts tumor energy supply and remodels the immunosuppressive TME. Furthermore, the resulting redox imbalance enhances copper-induced cuproptosis, eliciting a strong antitumor immune response. In tumor-bearing mice, CG@Cap demonstrated potent therapeutic efficacy, highlighting the promise of integrating immunometabolic reprogramming with cuproptosis induction for cancer therapy.
异常的糖酵解和谷氨酰胺代谢不仅维持肿瘤生长，还会对肿瘤微环境（TME）进行重编程。然而，由于代偿机制和低肿瘤免疫原性，靶向单一代谢途径往往不足以实现有效的癌症治疗。我们在此通过将谷氨酰胺代谢抑制剂与沸石咪唑酯骨架-8封装在一起，并在表面吸附葡萄糖氧化酶，随后与单宁酸和铜离子进行配位驱动组装，开发出了双饥饿治疗性金属酚纳米胶囊（CG@Cap）。纳米胶囊在肿瘤部位优先积累并被肿瘤细胞内化后，释放其所载物质，同时抑制糖酵解和谷氨酰胺代谢。这种双重抑制破坏了肿瘤的能量供应并重塑免疫抑制性TME。此外，由此产生的氧化还原失衡增强了铜诱导的铜死亡，引发强烈的抗肿瘤免疫反应。在荷瘤小鼠中，CG@Cap显示出强大的治疗效果，突出了将免疫代谢重编程与诱导铜死亡相结合用于癌症治疗的前景。
