Figure 2.

T cells remodel their metabolism to get differentiated into T-cell subsets within the TME. TN cells use glucose that enters in OXPHOS. Upon encountering cognate antigen, activated T cells get differentiated into TEFF, rapidly uptaking glucose and glutamine to perform aerobic glycolysis and generating lactate as a by-product. Once the antigen is cleared, TEFFs can get differentiated into memory T cells (TMEM), which depend on fatty acid oxidation. Equally, cancer cells depend on aerobic glycolysis and glutaminolysis that are fueled by glucose and glutamine, respectively, with production of lactate as a by-product. TEFF within the TME can be differentiated into Tregs with immunosuppressive properties that mainly produce energy by oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). T cells can become exhausted if they fail to clear antigens, as, for example, in cancer. T lymphocytes derived from tumors show elevated levels of PD-1 decreasing PI3K/Akt/mTOR signaling pathway and therefore glycolysis. Exhausted T cells in tumors having often dysfunctional mitochondria rely on FAO. FA: fatty acids. Cancer cells and T cells compete for nutrients, since cancer cells also have an increased glucose and glutamine uptake and they use aerobic glycolysis with production of lactate that is exported to the extracellular space, promoting acidification in the TME that compromises the activity of immune cells.