Immunometabolic Reprogramming of T Cells: Mitochondrial Dysfunction, Epigenetic Control, and Therapeutic Opportunities
Year: 2026
Type: article
Abstract: T lymphocytes must change their metabolic wiring to survive, expand, differentiate and persist, and the quality of that wiring increasingly appears to be a determinant of immune outcome rather than a passive by-product of activation. Naive cells rely on efficient mitochondrial oxidation, whereas activated effector cells switch to a program dominated by aerobic glycolysis, amino acid uptake and biosynthesis, and memory and regulatory subsets return to a more oxidative, lipid-supported state. Mitochondria sit at the centre of this circuit. They supply energy and biosynthetic intermediates, generate signalling reactive oxygen species, and provide substrates, such as acetyl-CoA, alpha-ketoglutarate and S-adenosylmethionine, that are used by chromatin-modifying enzymes. When mitochondrial mass, dynamics or respiratory capacity deteriorate under chronic antigen exposure, nutrient competition, hypoxia or inflammation, T cells lose fitness and enter dysfunctional states, including exhaustion and senescence. In parallel, epigenetic remodelling fixes these states and limits the durability of therapeutic reinvigoration. This review integrates current evidence on T-cell metabolic programs, mitochondrial function and failure, the metabolic-epigenetic interface, and the signalling nodes (mTOR, AMPK, HIF-1, Myc and PD-1) that coordinate them. We then discuss how these mechanisms shape autoimmune disease and tumour immunity, and we critically appraise therapeutic strategies, including metabolic inhibitors, mitochondrial enhancers, nutrient supplementation and engineering of cellular therapies. Finally, we outline outstanding challenges, including metabolic heterogeneity, systemic toxicity, translational gaps and the need for single-cell metabolic profiling.
Institution: Fergana Medical Institute of Public Health
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225320716