Extended Data Fig. 8. Schematic diagram of mechanisms underlying tumour suppression by cold exposure.

Under the thermoneutral temperature, cancer cells mainly acquire their energy through glycolysis, that is, the Warburg effect. Angiogenic vessels in tumours provide sufficient glucose for tumour consumption. Both WAT adipocytes (WAs) and BAT adipocytes (BAs) remain metabolically inert without significant glucose uptake and thermogenic activity. Glycolysis-generated ATP molecules and other metabolites support tumour cell proliferation at high rates. Under cold exposure, both sWAT and BAT undergo a browning process that markedly increases glucose uptake and thermogenesis. Owing to the elevated glucose uptake in activated BAT and sWAT, glucose uptake in tumours is significantly reduced. Consequently, tumour growth under cold exposure is inhibited through several possible mechanisms: 1) reduced glucose supply in tumours due to glucose redistribution in activated BAT and WAT; 2) mitigation of tumour hypoxia. Owing to limited glycolysis, acidosis and tumour hypoxia are reduced. Additionally, slow tumour growth also alleviates tumour hypoxia. Mitigation of tumour hypoxia by cold exposure also reduces expression levels of GLUTs, which are limiting factors for glucose uptake; and 3) plausible inhibition of glycolysis by lipid metabolites.