2. Academic Validation
  3. Nutrient transporter-oriented nanoinhibitor counteracts intracellular metabolic reprogramming for RT-resistant HCC treatment

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

  • Mater Today Bio. 2025 Feb 25:31:101608. doi: 10.1016/j.mtbio.2025.101608.
Yuehua Wang 1 2,  Zhenjie Wang 3,  Mengnan Liu 1,  Chaojie Chen 1,  Qiye Xi 4,  Jingwen Tang 1 2,  Zhiqiang Yu 5,  Shengtao Wang 6 7,  Ling Yu 8,  Meng Yu 4
Affiliations

Affiliations

  • 1 Department of General Surgery, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, China.
  • 2 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
  • 3 Office of Drug Clinical Trials, The People's Hospital of Gaozhou, Maoming, 525200, China.
  • 4 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 5 Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, 523018, China.
  • 6 School of Biomedical Engineering and Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, 215123, China.
  • 7 Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, 230026, China.
  • 8 Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
PMID: 40104639 DOI: 10.1016/j.mtbio.2025.101608
Abstract

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.

Keywords

Nanomedicine; ROS; Responsive drug release; Tumor microenvironment; Tumor therapy.

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