Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages
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<sup>+</sup> 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.
Authors
- Zhong-Zheng Zheng
- Haili Cheng (ORCID: https://orcid.org/0000-0002-1860-3585)
- Hui-Hui Hu (ORCID: https://orcid.org/0009-0007-0509-4762)
- Xianming Deng (ORCID: https://orcid.org/0000-0002-9354-5864)
- Dongxu Chen (ORCID: https://orcid.org/0000-0002-4357-2653)
- Sheng‐Cai Lin (ORCID: https://orcid.org/0000-0003-1993-8376)
- Jianfeng Wu (ORCID: https://orcid.org/0000-0002-9770-5538)
- Chen‐Song Zhang (ORCID: https://orcid.org/0000-0001-5218-0101)
- Jianyin Zhou (ORCID: https://orcid.org/0000-0002-4396-4518)
- Yu Chen (ORCID: https://orcid.org/0000-0003-4015-5181)
- Gang Chen (ORCID: https://orcid.org/0000-0003-2540-8232)
- Xuefeng Wang (ORCID: https://orcid.org/0000-0003-3613-6113)
- Hong Wen
- Zhenhua Wu (ORCID: https://orcid.org/0000-0003-4552-883X)
- Mengqi Li (ORCID: https://orcid.org/0000-0002-1171-5648)
- Jinhui Zhang (ORCID: https://orcid.org/0000-0002-1598-815X)
- Bin Lan (ORCID: https://orcid.org/0000-0003-3121-7643)
- Jie Lin (ORCID: https://orcid.org/0000-0003-3784-8120)
- Jingfeng Liu (ORCID: https://orcid.org/0000-0002-8509-0572)
- Jiazhou Chen (ORCID: https://orcid.org/0000-0001-7171-9547)
- Mingyang Yang (ORCID: https://orcid.org/0009-0006-7112-4838)
- Fuqing Chen
- Fangfang Chen (ORCID: https://orcid.org/0000-0002-5968-3542)
Institutions
- Fujian Medical University (CN)
- Xiamen University (CN)
- Henan University of Engineering (CN)
- Zhongshan Hospital of Xiamen University (CN)
- Fujian Provincial Cancer Hospital (CN)
Publication Details
- Journal
- Cell Research
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41422-025-01195-4
- Citations
- 4
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- Natural Science Foundation of Fujian Province
- Zhejiang University
- China Medical University
- Xiamen University
- Fujian Medical University
- Fonds Spéciaux de Recherche