Figure 1. Depletion of key nutrients and production of toxic by-products impair effector cells but support regulatory cells.

Beneficial cells, such as CD8⁺ and CD4⁺ effector T (Teff) cells, are depicted at left, and deleterious cells, including Tregs and TAMs, at right. Highly glycolytic tumor cells import glucose via GLUT1 and ferment it to lactate, which is coexported with protons into the TME via MCT1/MCT4. Glucose deprivation impairs the glycolytic capacity of Teff cells, which is key for their proliferation and translation of IFN-γ. Lactic acid impairs Teff cell proliferation by altering the NAD(H) redox balance. Utilization of lactic acid via MCT1 supports Treg proliferation and suppressive function. Lactic acid contributes to histone lactylation, which supports the expression of M2-like genes such as Arg1 in macrophages. Tryptophan is depleted via IDO expressed by MDSCs, TAMs, and tumor cells. Tryptophan depletion triggers the stress response kinase GCN2 and suppresses the mTOR pathway, reducing proliferation, altering memory differentiation, reducing activation of Teff cells, and inducing a regulatory phenotype in naive T cells. Kynurenine, imported via SLC7A5/8, engages with the AhR to increase PD-1 and Foxp3 expression. Kynurenine-induced ROS inhibit IL-2 signaling critical for T cell survival. Depletion of oxygen in the TME inhibits oxidative metabolism and decreases the mitochondrial mass of CD8⁺ T cells. ROS both intra- and extracellularly drive partnerless nuclear factor of activated T cells (NFAT) signaling and expression of PD-1 and Tim-3 in CD8⁺ T cells while promoting NFAT/Foxp3 signaling in Tregs. Oxygen depletion promotes extracellular accumulation of ATP, which is broken down to adenosine by the cell-surface ectonucleotidases CD39 and CD73. Adenosine acts through A2AR to impair IL-2 and IFN-γ production and increase PD-1 expression in Teff cells, while activating Foxp3 and CTLA4 expression to promote the development of Tregs.