Xie Qian, Sun Tao, Zhang Liang, Gong Mingfu, Zhang Wansu, Liu Xu, Zhao Yue, Wang Miaomiao, Yang Xiaofeng, Zhang Zhipeng, Liu Gang, Zhou Chunyu, Zhang Dong
Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China; Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China.
Biomaterials. 2025 Apr;315:122971. doi: 10.1016/j.biomaterials.2024.122971. Epub 2024 Nov 19.
Abnormal tumor metabolism leads to tumor growth, metastasis, and recurrence, reprogramming tumor metabolism and activating potent anti-tumor immune response have been demonstrated to have good therapeutic effects on tumor elimination. Copper-based nanomaterials involved in cuproptosis show great prospects in these two aspects, but their efficiency is restricted by Cu homeostasis and the toxicity of the chelator. Here, the pH-responsive AuNRs@CuO core-shell plasmonic hybrid nanorods (ACNRs) have been successfully fabricated to realize microenvironment-controlled release at the tumor site for the combined therapy of cuproptosis and photothermal treatment. The AuNRs core exhibited excellent NIR-II photothermal property, which boost the intracellular concentration of copper to trigger severe cuproptosis and induce immunogenic cell death of tumor cells. In vivo studies demonstrated the ACNR exhibited efficient tumor therapy for primary, metastatic, and recurrent tumors. ACNRs-induced cuproptosis and PTT were capable of reprogramming energy metabolism, leading to a decreased production of lactic acid. This potential of metabolic reprogramming assisted in reshaping the immunosuppressive tumor microenvironment to facilitate the infiltration of immune cells and boost the immune responses triggered by PTT. The therapeutic mechanism was further verified by metabolomics analysis, which indicated that ACNRs + PTT treatment led to the inhibition of the Pentose Phosphate Pathway and Glycolysis pathways in tumor cells. The suppression of glycolytic reduced ATP synthesis, thereby hindering energy-dependent copper efflux, which in turn promoted cuproptosis. Taken together, this study offers promising insights for cuproptosis-based cancer treatment and sheds new light on nanomedicine-mediated metabolic modulation for future tumor therapy.
异常的肿瘤代谢会导致肿瘤生长、转移和复发，重编程肿瘤代谢并激活强大的抗肿瘤免疫反应已被证明对消除肿瘤具有良好的治疗效果。参与铜死亡的铜基纳米材料在这两个方面显示出巨大的前景，但其效率受到铜稳态和螯合剂毒性的限制。在此，成功制备了pH响应性的金纳米棒@氧化铜核壳等离子体混合纳米棒（ACNRs），以实现肿瘤部位的微环境控制释放，用于铜死亡和光热治疗的联合治疗。金纳米棒核心表现出优异的近红外二区光热性能，可提高细胞内铜的浓度，引发严重的铜死亡并诱导肿瘤细胞的免疫原性细胞死亡。体内研究表明，ACNRs对原发性、转移性和复发性肿瘤均表现出高效的肿瘤治疗效果。ACNRs诱导的铜死亡和光热治疗能够重编程能量代谢，导致乳酸产生减少。这种代谢重编程的潜力有助于重塑免疫抑制性肿瘤微环境，促进免疫细胞浸润，并增强光热治疗引发的免疫反应。代谢组学分析进一步验证了治疗机制，结果表明ACNRs + 光热治疗导致肿瘤细胞中磷酸戊糖途径和糖酵解途径受到抑制。糖酵解的抑制减少了ATP合成，从而阻碍了能量依赖性铜外流，进而促进了铜死亡。综上所述，本研究为基于铜死亡的癌症治疗提供了有前景的见解，并为未来肿瘤治疗中纳米医学介导的代谢调节提供了新的思路。
