Fig 1.
Metabolic reprogramming in cancer cells.
Glucose metabolism involves both glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. Cancer cells preferentially adopt aerobic glycolysis, enabling rapid energy production and biosynthesis while contributing to immune evasion. To improve the effectiveness of immunotherapy, strategies to reprogram the tumor microenvironment (TME) are under investigation. Four key intervention points within the glycolytic pathway have been identified: targeting glucose uptake, inhibiting critical glycolytic enzymes, blocking lactate production and blocking lactate export. 3PG, 3-phosphoglyceric acid; ATP, adenosine triphosphate; CoA, coenzyme-A; F1,6 BP, fructose 1,6-bisphosphate; F6P, fructose 6-phosphate; F2,6 BP, fructose 2,6-bisphosphate; G6P, glucose 6-phosphate; α-KG, α-ketoglutarate; PDH, pyruvate dehydrogenase; PPP, pentose phosphate pathway. Figure created with BioRender, https://www.biorender.com.
Fig 2.
Metabolic characteristics during T cell differentiation.
Upon activation, naïve T cells undergo metabolic reprogramming and differentiate into effector T cells, shifting toward aerobic glycolysis to support rapid proliferation and effector functions. This transition is accompanied by epigenetic modifications at key gene loci. Following antigen clearance, a subset of T cells differentiates into memory T cells, which revert to utilizing fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to support long-term survival and functional readiness. By contrast, during chronic antigen stimulation, effector T cells are driven toward an exhausted state, characterized by metabolic reprogramming, mitochondrial dysfunction and impaired effector function. Regulatory T cells (Tregs), an immunosuppressive population that supports tumor progression, rely on OXPHOS and FAO for survival and exert their function through the secretion of inhibitory cytokines such as TGF-β and IL-10. ATP, adenosine triphosphate; BCAA, branched-chain amino acid; CTLA4, cytotoxic T-lymphocyte associated protein 4; FOXO1, forkhead box O1; FOXP3, forkhead box P3; GLUT-1, glucose transporter 1; HIF-1α, hypoxia-inducing factor 1α; mTOR, mammalian target of rapamycin; PD-1, programmed cell death protein 1; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1-α; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle; TCR, T cell receptor. Figure created with BioRender, https://www.biorender.com.
Fig 3.
Metabolic interplay of cancer cells and T cells in the TME.
The tumor microenvironment (TME) is enriched with immunosuppressive cell populations such as regulatory T cells (Tregs), which promote tumor progression and suppress anti-tumor immunity through metabolic reprogramming and the secretion of inhibitory factors, such as TGF-β and IL-10. Tumor cells further contribute to immune dysfunction by outcompeting effector T cells for critical nutrients, including oxygen, glucose and amino acids, thereby impairing T cell infiltration, effector function and cytotoxicity. Moreover, the accumulation of tumor-derived metabolites such as lactate, which suppresses T cell proliferation and function, yet may support T cell stemness, profoundly reshapes the immune landscape. Additional metabolites, including kynurenine, fumarate and succinate, further contribute to CD8+ T cell dysfunction and exhaustion. Collectively, these factors establish a metabolically hostile and immunosuppressive milieu that impairs effective antitumor immune responses. MCT, monocarboxylate transporter; PD-1, programmed cell death protein 1; PGE2, prostaglandin E2. Figure created with BioRender, https://www.biorender.com.