Glucose starvation mimetic aldometanib removes immune barrier  allowing hepatocellular carcinoma mice to live to normal ages (PRJCA031116)
Dysregulated metabolism in tumour tissues, and para-tumour 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 therapeutic effect on cancers using hepatocellular carcinomas (HCC) as models, by aldometanib that specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates the lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinomas (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature  ages, although aldometanib does not possess cytotoxicity towards HCC  or normal cells. Intriguingly, aldometanib exerts the anti-cancer efficacy only in immune-potent  host mice, but not in immune-defective mice. We have further found that aldometanib treatment renders HCC tissues infiltrated by CD8+ T cells. Our findings have thus suggested that the metabolic regulator AMPK rebalances the tumour microenvironment to allow the innate immune cells  to eliminate cancer cells. Moreover, we have demonstrated that metabolic intervention can make cancer a lifelong manageable disease, ushering in a new direction for cancer therapy.