Volume 35, No 12, Dec 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 12, December 2025: 934-953   |  Open Access

ORIGINAL ARTICLES

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

Hui-Hui Hu^1,† , Xuefeng Wang^2,† , Bin Lan^2,† , Haili Cheng² , Hong Wen² , Fangfang Chen² , Jianfeng Wu³ , Mengqi Li¹ , Jiazhou Chen¹ , Jinhui Zhang⁴ , Dongxu Chen¹ , Shiyu Lin¹ , Jieyu Lin² , Mingyang Yang¹ , Zhenhua Wu¹ , Zhong-Zheng Zheng¹ , Fuqing Chen⁵ , Jianyin Zhou⁵ , Gang Chen² , Yu Chen² , Xianming Deng^1,6 , Chen-Song Zhang^1,4,6,* , Jingfeng Liu^2,* , Sheng-Cai Lin^1,4,6,*

¹State 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
²Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
³Laboratory Animal Research Centre, Xiamen University, Xiamen, Fujian, China
⁴The Zhongzhou Laboratory for Integrative Biology, School of Basic Medical Sciences, Henan University, Zhengzhou, Henan, China
⁵Department 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
⁶Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
^†These authors contributed equally: Hui-Hui Hu, Xuefeng Wang, Bin Lan
Correspondence: Chen-Song Zhang(cszhang@xmu.edu.cn)Jingfeng Liu(drjingfeng@fjmu.edu.cn)Sheng-Cai Lin(linsc@xmu.edu.cn)

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.

https://doi.org/10.1038/s41422-025-01195-4

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