Fig. 3

Lipid metabolism reprogramming promotes Tregs adaptation in TME. In the tumor microenvironment, most of the glucose and oxygen transported by disordered vessels are taken up by tumor cells, resulting in a hypoxia and glucose deprivation microenvironment, and the production of large amounts of lactate is detrimental to immune cell survival. Tumor-associated adipocytes are activated and promote lipid accumulation. Tregs highly express membrane receptor CD36 to uptake lipids and activate the PPAR-β pathway to enhance lipid utilization. Foxp3 expression also promotes lipid oxidation and interacts with Myc to regulate lactate dehydrogenase reaction direction, resisting the harmful effects of lactic acid accumulation. LKB1 prevents STAT4 activation-dependent CNS2 methylation of Foxp3, thereby preventing its destabilization. LKB1 also activates AMPK to inhibit mTORC1 pathway-mediated glycolysis. Under hypoxic conditions, activated HIF-1α enhances lipid metabolism and Fxop3 expression. CTLA-4 signaling activates PTEN to inhibit the mTOR pathway. Activation of the mevalonate pathway upregulates SREBP-mediated PD-1 expression, as well as RAS-STAT5-dependent Foxp3 expression