Nutrient deprivation and lipid accumulation limit T cell function. (A) Intercellular competition for nutrients can limit T cell function. Tumor cells compete with immune cells for glucose, glutamine, and methionine in the TME, leading to nutrient deprivation that directly inhibits T cells, or indirectly inhibits T cells by negatively affecting the functionality of cDC1s. In contrast, metabolic adaptation of Treg cells allow the cells to maintain their suppressive capacity in conditions of low glucose and high lactate in the TME. IDO-expressing pDCs help maintain Treg suppressive function. Further, IDO and ARG1-expressing DCs and TAMs, and IDO-expressing MDSCs, catabolize tryptophan and arginine, leading to localized depletion. Consequently, T cell function is impaired. (B) Lipids, including fatty acids and cholesterol, accumulate in the TME. CD8⁺ T cells in the TME increase the uptake of oxidized low-density lipoprotein (OxLDL) by CD36, leading to greater lipid peroxidation, p38 kinase activation and ferroptosis. Further, increased intracellular cholesterol in CD8⁺ T cells promotes ER stress–XBP1 signaling and coinhibitory receptor expression, including PD-1 and 2B4. Together, increased cholesterol and fatty acids induce CD8⁺ T cell dysfunction in the TME. However, increased CD36 expression on intratumoral Treg cells correlates with increased lipid uptake and mitochondrial fitness and persistence via PPAR-β signaling. Treg cell accumulation in the TME may further impair T cell function and antitumor immunity.