Synergistic enhancement of low-dose radiation therapy via cuproptosis and metabolic reprogramming for radiosensitization in in situ hepatocellular carcinoma

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.