IMMUNOMETABOLISM AS A CENTRAL REGULATOR OF HEALTH AND DISEASE: INTEGRATING METABOLIC SIGNALING, CELLULAR PLASTICITY, AND THERAPEUTIC OPPORTUNITIES

Immunometabolism has emerged as a central regulatory framework linking systemic metabolic status, intracellular metabolic pathways, immune-cell identity, tissue microenvironment, and disease progression. Rather than serving solely as a source of cellular energy, metabolism actively regulates immune-cell activation, differentiation, effector function, memory formation, tolerance, and inflammatory adaptation through nutrient sensing, mitochondrial activity, metabolite signaling, and metabolic–epigenetic interactions. This review integrates current concepts concerning the metabolic programming of T cells, macrophages, dendritic cells, natural killer cells, B cells, and other immune populations, emphasizing the dynamic and context-dependent nature of immunometabolic plasticity. Particular attention is given to major regulatory networks involving glycolysis, oxidative phosphorylation, fatty-acid metabolism, amino-acid utilization, mTOR, AMPK, HIF-1α, and immunoregulatory metabolites such as succinate, itaconate, lactate, and short-chain fatty acids. The tissue metabolic microenvironment—including nutrient competition, hypoxia, acidosis, lipid availability, stromal interactions, and microbiota-derived metabolites—is discussed as a major determinant of immune function in health and disease. The review further examines immunometabolic dysregulation in obesity, diabetes, atherosclerosis, cancer, autoimmunity, infection, sepsis, aging, and neuroinflammation. Emerging therapeutic opportunities involving metabolic inhibitors, nutrient-sensing pathways, metabolite-based interventions, dietary modulation, microbiome manipulation, and cancer immunotherapy are considered alongside challenges related to specificity, tissue heterogeneity, and clinical translation. Finally, advances in single-cell analysis, spatial profiling, metabolic flux analysis, multi-omics, and computational systems biology are highlighted as essential for developing precision immunometabolism. Collectively, immunometabolism represents a dynamic systems-level interface between metabolism and immunity with substantial implications for disease mechanisms, biomarkers, and therapeutic development.