Amino acid metabolism in the TIME. (IMAGE)
Caption
Amino acid metabolism in the TIME. The TIME is shaped by metabolic competition between tumor and immune cells. Amino acids have key roles in modulating immune responses and tumor progression. (A) Glutamine: tumor cells upregulate the glutamine transporter, SLC1A5, increasing glutamine uptake to fuel the TCA cycle and promote PD-L1 expression. PD-L1 on tumor cells interacts with PD-1 receptors on CD8⁺ T cells, inhibiting TCR signaling initiated by MHC I–TCR antigen presentation and thereby suppressing T cell activation and inducing exhaustion. Excessive glutamine uptake by tumor cells reduces glutamine availability in the microenvironment, thereby limiting TCA cycle activity and metabolic fitness in T cells. (B) Tryptophan: tumor cells overconsume tryptophan and convert tryptophan into kynurenine via IDO. Kynurenine activates AhR signaling in T cells, which leads to downregulation of co-stimulatory molecules (e.g., CD80/CD86) and upregulation of PD-1, thereby suppressing T cell activation and fostering an immunosuppressive microenvironment. (C) Serine: tumor cells excessively uptake serine to fuel SGOC metabolism via ATF4, supporting nucleotide biosynthesis and proliferation. In contrast, serine deprivation promotes M1 macrophage polarization by upregulating IGF1 and activating STAT1 signaling. (D) Arginine: TAMs and MDSCs express ARG1 to deplete extracellular arginine and produce NO, both contributing to immune suppression. Tregs secrete IL-10 and TGF-β, further reinforcing immunosuppression and shaping the TIME. The figure was created with BioRender.com. AhR, aryl hydrocarbon receptor; ARG1, arginase-1; ATF4, activating transcription factor 4; CD80, cluster of differentiation 80; CD86, cluster of differentiation 86; IDO, indoleamine 2,3-dioxygenase; IGF1, insulin-like growth factor 1; IL-10, interleukin-10; Kyn, kynurenine; MDSC, myeloid-derived suppressor cell; NO, nitric oxide; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SGOC, serine–glycine–one-carbon; SLC, solute carrier; STAT1, signal transducer and activator of transcription 1; TAM, tumor-associated macrophage; TCR, T cell receptor; TGF-β, transforming growth factor-beta; TIME, tumor immune microenvironment; Treg, regulatory T cell.
Credit
Cancer Biology & Medicine
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