Glycolytic metabolism as a central regulator of T cell fate and function in the tumor microenvironment

Abstract T cells are the central effectors of antitumor immunity, yet their function is profoundly constrained by the metabolically hostile tumor microenvironment (TME). In order to meet the bioenergetic and biosynthetic demands of activation and differentiation, T cells undergo metabolic reprogramming, particularly enhanced glycolysis, upon antigen recognition. However, intratumoral glucose deprivation and lactate accumulation driven by the Warburg effect of cancer cells create a metabolic tug-of-war that differentially impacts T cell subsets. The present review systematically elucidates how glycolytic metabolism governs the fate and function of CD4⁺ T cells, CD8⁺ T cells, regulatory T cells (Tregs), and CAR-T cells within the TME. It highlights the striking metabolic dichotomy between effector T cells that depend on aerobic glycolysis and Tregs, which exhibit metabolic plasticity enabling them to thrive under nutrient-limited conditions. Key signaling nodes, including calcium-NFAT, CD38/NAD⁺/SIRT1, MAPK/AP1, and PI3K/Akt/mTOR, converge to integrate microenvironmental cues with transcriptional and epigenetic programs that shape T cell immunity. The report also discusses how shared metabolic mechanisms intersect with synthetic receptor architecture to influence persistence and exhaustion in CAR-T cells. By exploring recent advances, this review aims to provide a framework for targeting glucose metabolism to enhance antitumor immune responses and optimize next-generation immunotherapies.