Nutrient transporter-oriented nanoinhibitor counteracts intracellular metabolic reprogramming for RT-resistant HCC treatment.

Radiotherapy (RT) is the primary treatment modality for hepatocellular carcinoma (HCC). Inevitably, the X-ray exposure also increases the metabolic stress and energy demands in surviving tumor cells, which leads to metabolic reprogramming that reduces the sensitivity of HCC to clinical treatments including RT. Nevertheless, the current research in tumor metabolic therapy predominantly focuses on inhibiting glycolytic pathways, and the consequent metabolic compensation behavior of tumor cells exacerbates the risks of drug resistance and recurrence. To address this challenge, we innovatively proposed a tumor-specific multi-metabolic pathway regulation strategy navigated by tumor cell surface nutrient transporter (2-DG/BP MRs), which can be triggered by X-ray radiation to achieve dual blockade of glycolysis and glutamine metabolism pathways. Thus, this nanosystem reconfigured metabolic pathways within tumor cells to counteract RT-induced metabolic reprogramming through dual metabolic inhibition (glycolysis and glutamine metabolism). This approach disrupted the essential energy supply required for cancer cell proliferation without causing metabolic disorders in normal cells, thereby sensitizing HCC to RT. This tumor cell-specific metabolic intervention strategy provides a safe and effective approach for combination therapy in clinically RT-resistant tumors.