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  3. Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages

Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages

  • Cell Res. 2025 Dec;35(12):934-953. doi: 10.1038/s41422-025-01195-4.
Hui-Hui Hu # 1,  Xuefeng Wang # 2,  Bin Lan # 2,  Haili Cheng 2,  Hong Wen 2,  Fangfang Chen 2,  Jianfeng Wu 3,  Mengqi Li 1,  Jiazhou Chen 1,  Jinhui Zhang 4,  Dongxu Chen 1,  Shiyu Lin 1,  Jieyu Lin 2,  Mingyang Yang 1,  Zhenhua Wu 1,  Zhong-Zheng Zheng 1,  Fuqing Chen 5,  Jianyin Zhou 5,  Gang Chen 2,  Yu Chen 2,  Xianming Deng 1 6,  Chen-Song Zhang 7 8 9,  Jingfeng Liu 10,  Sheng-Cai Lin 11 12 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, State-Province Joint Engineering Research Center of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2 Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
  • 3 Laboratory Animal Research Centre, Xiamen University, Xiamen, Fujian, China.
  • 4 The Zhongzhou Laboratory for Integrative Biology, School of Basic Medical Sciences, Henan University, Zhengzhou, Henan, China.
  • 5 Department of Hepatobiliary Surgery, Xiamen Key Laboratory of Translational Medicine for Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.
  • 6 Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.
  • 7 State Key Laboratory of Cellular Stress Biology, State-Province Joint Engineering Research Center of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 8 The Zhongzhou Laboratory for Integrative Biology, School of Basic Medical Sciences, Henan University, Zhengzhou, Henan, China. [email protected].
  • 9 Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China. [email protected].
  • 10 Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China. [email protected].
  • 11 State Key Laboratory of Cellular Stress Biology, State-Province Joint Engineering Research Center of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 12 The Zhongzhou Laboratory for Integrative Biology, School of Basic Medical Sciences, Henan University, Zhengzhou, Henan, China. [email protected].
  • 13 Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 41286115 DOI: 10.1038/s41422-025-01195-4
Abstract

Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie Cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8+ T cells, which was not seen in mice with liver-specific knockout of AMPKα. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate Cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make Cancer a lifelong manageable disease may usher in a new era of Cancer therapy.

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