Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity

Abstract

T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.

Keywords: T cell; T cell metabolism; anti-tumor function; tumor microenvironment.

Figure 1

T-cell metabolism in the TME. The nutrients (glucose, fatty acids, and amino acids) in the TME are lacking due to tumor cells or immunosuppressive cells, leading to abnormal metabolism of T cells. Glucose and fatty acids are used in large quantities by tumor cells for proliferation, while the metabolism of glucose and fatty acids is restricted in the T cells that infiltrated the TME to reduced anti-tumor response. Immune checkpoints (PD-1 and CTLA-4) also inhibit glycolysis in the T cells that infiltrated the TME. ROS, kynurenine, PUFA, and OXLDL are enriched in TME to induce T cell ferroptosis and exhaustion. Hypoxia and exosome in TME inhibit PGC1α activation to damage T-cell anti-tumor function. Cysteine, arginine, and methionine are competitively ingested by tumor cells or monocytes to inhibit the T-cell anti-tumor response. ATP in TME is hydrolyzed by CD39 and CD73 to produce adenosine, which decreases the T-cell anti-tumor function through A2AR. Accumulated cholesterol in TME inhibits T-cell function through ER stress, and increased cholesterol esterification in T cells restricts the T-cell anti-tumor response. 5-HTP, 5-hydroxytryptophan—A2AR, A2A receptor—ER, endoplasmic reticulum—IDO, indoleamine 2,3-dioxygenase—OXLDL, oxidized low-density lipoproteins—PGC1α, PPAR-γ co-activator 1α—PUFA, poly-unsaturated fatty acids—ROS, reactive oxygen species—SAM, s-adenosylmethionine—TME, tumor microenvironment.

Figure 2

Metabolic intervention strategy for improving the anti-tumor response of T cells. The interventions of glucose, lipid, amino acid, and nucleotide metabolism have been used to enhance T-cell anti-tumor responses. A2AR, A2A receptor—IDO, indoleamine 2,3-dioxygenase—LDH, Lactate dehydrogenase—PGC1α, PPAR-γ co-activator 1α.