Hui-Hui Hu, Xuefeng Wang, Bin Lan, Haili Cheng, Hong Wen, Fangfang Chen, Jianfeng Wu, Mengqi Li, Jiazhou Chen, Jinhui Zhang, Dongxu Chen, Shiyu Lin, Shiyu Lin, Jieyu Lin, Mingyang Yang, Zhenhua Wu, Zhong-Zheng Zheng, Fuqing Chen, Jianyin Zhou, Yu Chen, Yu Chen, Xianming Deng, Chen‐Song Zhang, Sheng‐Cai Lin, Sheng‐Cai Lin, Sheng‐Cai Lin
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.