Shao Ni, Yang Yongqing, Hu Genwen, Luo Qiao, Cheng Nianlan, Chen Jifeng, Huang Yanyu, Zhang Hong, Luo Liangping, Xiao Zeyu
The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Department of Radiology and Nuclear Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
Department of Radiology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, 518020, China.
J Nanobiotechnology. 2024 Dec 19;22(1):772. doi: 10.1186/s12951-024-03011-4.
Radiotherapy (RT) is a primary clinical approach for cancer treatment, but its efficacy is often hindered by various challenges, especially radiation resistance, which greatly compromises the therapeutic effectiveness of RT. Mitochondria, central to cellular energy metabolism and regulation of cell death, play a critical role in mechanisms of radioresistance. In this context, cuproptosis, a novel copper-induced mitochondria-respiratory-dependent cell death pathway, offers a promising avenue for radiosensitization.
In this study, an innovative theranostic nanoplatform was designed to induce cuproptosis in synergy with low-dose radiation therapy (LDRT, i.e., 0.5-2 Gy) for the treatment of in situ hepatocellular carcinoma (HCC). This approach aims to reverse the hypoxic tumor microenvironment, promoting a shift in cellular metabolism from glycolysis to oxidative phosphorylation (OXPHOS), thereby enhancing sensitivity to cuproptosis. Concurrently, the Fenton-like reaction ensures a sustained supply of copper and depletion of glutathione (GSH), inducing cuproptosis, disrupting mitochondrial function, and interrupting the energy supply. This strategy effectively overcomes radioresistance and enhances the therapeutic efficacy against tumors.
In conclusion, this study elucidates the intricate interactions among tumor hypoxia reversal, cuproptosis, metabolic reprogramming, and radiosensitization, particularly in the context of treating in situ hepatocellular carcinoma, thereby providing a novel paradigm for radiotherapy.
放射治疗（RT）是癌症治疗的主要临床方法，但其疗效常常受到各种挑战的阻碍，尤其是辐射抗性，这极大地损害了放射治疗的治疗效果。线粒体是细胞能量代谢和细胞死亡调节的核心，在辐射抗性机制中起着关键作用。在这种情况下，铜死亡是一种新的铜诱导的线粒体呼吸依赖性细胞死亡途径，为放射增敏提供了一条有前景的途径。
在本研究中，设计了一种创新的诊疗纳米平台，与低剂量放射治疗（LDRT，即0.5 - 2 Gy）协同诱导铜死亡，用于治疗原位肝细胞癌（HCC）。这种方法旨在逆转缺氧肿瘤微环境，促进细胞代谢从糖酵解向氧化磷酸化（OXPHOS）转变，从而增强对铜死亡的敏感性。同时，类芬顿反应确保铜的持续供应和谷胱甘肽（GSH）的消耗，诱导铜死亡，破坏线粒体功能，并中断能量供应。该策略有效地克服了辐射抗性，提高了对肿瘤的治疗效果。
总之，本研究阐明了肿瘤缺氧逆转、铜死亡、代谢重编程和放射增敏之间的复杂相互作用，特别是在治疗原位肝细胞癌的背景下，从而为放射治疗提供了一种新的范例。
