Fig. 5

A schematic overview of the influence of the TME on TI-Treg proliferation and function through metabolic reprogramming. 1 The “Warburg effect” characterizes the TME as glucose-deficient and lactate-accumulative. The role of glycolysis in TI-Treg function is controversial, but it is clear that MCT1-induced lactate uptake is increased in Tregs. Lactate is not only converted to pyruvate by LDH to enter the TCA cycle, but is also used for the production of PEP, which serves as an intermediate for glycolysis. 2 FAO and FAS are both active in TI-Tregs. Since FFA availability is upregulated in the TME, the uptake of FA and subsequent FAO are increased with the support of FABPs and CD36. CD36-induced FFA uptake also activates PPAR-β signaling, which promotes mitochondrial fitness and increases the NAD-to-NADH ratio. The mevalonate pathway and FAS are supported by SCAP/SREBP signaling. 3 TI-Tregs show high OXPHO and ROS production, which can be scavenged by GSH. IDO is enriched in the TME, and the IDO-catalyzed tryptophan metabolite kynurenine curbs the infiltration of Teffs by binding to AHR, thus promoting the generation of Tregs by inducing tolerogenic dendritic cells. 4 The hypoxic TME activates the HIF-1α pathway, which promotes glycolysis. The activity of mTOR-HIF-1α is inhibited by TLR8. Until now, the correlation between HIF-1α and Foxp3 expression remains controversial. MCT1 monocarboxylate transporter 1, LDH lactate dehydrogenase, PEP phosphoenolpyruvate, FABP fatty acid-binding protein, SREBP sterol regulatory element-binding protein, SCAP SREBP cleavage-activating protein, IDO indoleamine 2,3-dioxygenase, AHR aryl hydrocarbon receptor, MDSC myeloid-derived suppressive cells, TAM tumor-associated fibroblasts