Metabolic regulation of the immune system in disease
How metabolic pathways shape immune cell fate and drive inflammation, immune dysfunction, and disease progression across cancer, autoimmunity, and metabolic disorders.
Immunometabolism is the field that examines how intracellular metabolic pathways regulate immune cell fate, function, and effector output, and how immune activity in turn reshapes systemic and tissue metabolism. It positions metabolism as an active regulator of immunity rather than a passive consequence of activation.¹
Metabolism as an active regulator of immunity
Immune cells are among the most metabolically plastic cells in the body. Their capacity to sense nutrients, oxygen, and inflammatory cues allows them to rapidly reconfigure bioenergetic and biosynthetic pathways in ways that dictate whether they proliferate, differentiate, mount effector responses, or enter regulatory and memory states.¹,²
This plasticity is essential because immune responses impose sharply different demands at different phases. Quiescent lymphocytes require efficient ATP generation for surveillance, while activated effectors need rapid biomass accumulation for clonal expansion and cytokine synthesis. Memory and regulatory populations, in contrast, depend on sustained mitochondrial fitness to persist long-term.²,³
Crucially, the relationship between metabolism and immunity is bidirectional. Metabolic pathways shape immune cell decisions, but immune-driven inflammation also remodels systemic metabolism through cytokine signaling, altered nutrient partitioning, and changes to tissue microenvironments. When this crosstalk becomes dysregulated, it can drive chronic inflammation and disease progression.¹,⁴
Core metabolic pathways shaping immune cell function
Several interconnected pathways integrate environmental signals with cell-intrinsic programs to determine immune phenotype. Rather than acting in isolation, they operate as a network in which the balance between catabolic and anabolic activity governs functional identity.
Glycolysis and the inflammatory program
Aerobic glycolysis, the conversion of glucose to lactate even under oxygen-sufficient conditions, is a hallmark of activated effector T cells, inflammatory (M1-like) macrophages, and mature dendritic cells. Although less efficient than oxidative phosphorylation for ATP yield, glycolysis rapidly supplies biosynthetic intermediates for nucleotide, amino acid, and lipid synthesis, supporting proliferation and cytokine output.²,⁷
Glycolytic intermediates also act as signaling molecules. For example, accumulation of succinate and citrate in inflammatory macrophages stabilizes HIF-1α and drives IL-1β production, linking central carbon metabolism directly to inflammatory gene expression.²
Oxidative phosphorylation and mitochondrial fitness
Mitochondrial oxidative phosphorylation (OXPHOS) dominates in naïve, memory, and regulatory immune populations. Beyond ATP generation, mitochondria regulate immune fate through reactive oxygen species (ROS) signaling, calcium handling, and the release of metabolites that shape epigenetic programs.³
Mitochondrial fitness, encompassing membrane potential, biogenesis, and dynamics, is now recognized as a determinant of memory T-cell longevity and regulatory T-cell (Treg) stability. Loss of mitochondrial integrity is linked to exhaustion phenotypes and impaired immune persistence.³,⁷
Lipid metabolism
Fatty acid oxidation (FAO) supports the energetic needs of memory T cells, Tregs, and alternatively activated (M2-like) macrophages, while fatty acid synthesis (FAS) fuels the membrane expansion and lipid signaling required by proliferating effectors and dendritic cells.²,⁵
Cholesterol and phospholipid metabolism further influence membrane composition, receptor clustering, and inflammasome activation, linking lipid handling to both innate sensing and adaptive differentiation.
Amino acid metabolism and nutrient sensing
Amino acids act as both substrates and signaling cues. Glutamine fuels anaplerosis and nucleotide synthesis in proliferating lymphocytes; arginine availability shapes macrophage polarization and T-cell effector capacity; and tryptophan catabolism, particularly via indoleamine 2,3-dioxygenase (IDO), generates kynurenine metabolites that promote immune tolerance.¹,⁷
These inputs converge on nutrient-sensing hubs, most notably mTORC1, which promotes anabolic effector programs, and AMPK, which favors catabolic, regulatory, and memory states. The balance between these sensors is a central axis controlling immune cell fate.²,⁷
How do metabolic programs determine immune cell identity?
Metabolic programs determine immune cell identity by coupling nutrient availability and signaling inputs to transcriptional and epigenetic machinery. Shifts between glycolysis, OXPHOS, and FAO are not merely energetic choices, they generate distinct metabolite pools that modify chromatin, control transcription factor activity, and lock cells into specific functional states.²,⁷
For example, acetyl-CoA levels influence histone acetylation at effector gene loci, while α-ketoglutarate and succinate modulate the activity of chromatin-modifying enzymes. In this way, metabolic flux directly imprints on the epigenome, stabilizing phenotypes such as Th17 versus Treg differentiation or M1 versus M2 macrophage polarization.²
Immunometabolism across disease states
Metabolic dysregulation is a shared feature of many diseases, though the mechanisms and consequences differ substantially by context. Across settings, disease-associated metabolic remodeling can either amplify pathological immunity or blunt protective responses.
Autoimmunity (e.g., SLE, RA)
Cancer
Within the tumor microenvironment, cancer cells and immune cells compete for glucose, glutamine, and amino acids. Tumor-driven nutrient depletion and accumulation of immunosuppressive metabolites such as lactate and kynurenine impair effector T-cell function and promote exhaustion, blunting responses to immunotherapy.⁴
Autoimmunity
In autoimmune disease, immune cells often show sustained glycolytic activity and mitochondrial abnormalities that reinforce pathogenic effector programs. Altered lipid handling and dysregulated nutrient sensing further contribute to the persistence of autoreactive T and B cells and inflammatory myeloid populations.⁴,⁶
Obesity and meta-inflammation
Chronic nutrient excess reshapes adipose tissue-resident immune populations, shifting macrophages toward inflammatory phenotypes and disrupting local Treg networks. The resulting low-grade systemic inflammation contributes to insulin resistance and heightened susceptibility to metabolic and inflammatory complications.⁵,⁷
Why is immunometabolism a priority for therapeutic research?
Immunometabolism is a therapeutic priority because metabolic pathways are both druggable and functionally decisive. Targeting metabolic nodes offers a way to reprogram immune responses, dampening pathological inflammation, restoring exhausted effector function, or reinforcing regulatory populations, without broadly suppressing immunity.¹,⁴
This has driven interest in strategies that modulate glycolysis, mitochondrial function, lipid handling, and amino acid catabolism to enhance immunotherapy responses in cancer, restore tolerance in autoimmunity, and resolve chronic inflammation in metabolic disease. Immunometabolic biomarkers are also emerging as tools for patient stratification and monitoring.⁴,⁶
Exploring immunometabolism in major diseases
This article series examines how metabolic pathways shape immune responses across five disease areas, each highlighting distinct mechanisms and translational opportunities:
- Immunometabolism in cancer — how metabolic competition within the tumor microenvironment influences immune surveillance, immune escape, and response to immunotherapy.
- Immunometabolism in systemic lupus erythematosus (SLE) — metabolic abnormalities that sustain autoreactive immune responses and systemic inflammation.
- Immunometabolism in rheumatoid arthritis (RA) — how metabolic reprogramming drives synovial inflammation and joint destruction.
- Immunometabolism in multiple sclerosis (MS) — the metabolic mechanisms underlying neuroinflammation and immune-mediated CNS damage.
- Immunometabolism in obesity — the link between nutrient excess, immune dysfunction, and chronic metabolic inflammation.
Together, these articles illustrate how immunometabolism is reshaping our understanding of disease mechanisms and opening new avenues for biomarker discovery and therapeutic innovation.
FAQs
What is the difference between immunometabolism and general cellular metabolism?
Immunometabolism specifically examines how metabolic pathways regulate immune cell activation, differentiation, and effector function, and how immune signaling reshapes systemic metabolism. While it draws on the same core biochemistry as general cellular metabolism, its focus is on the bidirectional interplay between metabolic flux and immune identity.¹,²
Why do activated immune cells favor glycolysis over more efficient oxidative phosphorylation?
Activated immune cells favor glycolysis because it rapidly supplies biosynthetic intermediates needed for proliferation and cytokine production, even though it yields less ATP per glucose molecule. Glycolytic intermediates also serve as signaling molecules that reinforce inflammatory transcriptional programs, making glycolysis a functional as well as energetic choice.²,⁷
Can targeting immune cell metabolism treat disease without broad immunosuppression?
Emerging evidence suggests that selectively modulating metabolic nodes, such as specific amino acid pathways or mitochondrial function, can reprogram pathogenic immune subsets while preserving protective immunity. This selectivity is a key advantage over conventional immunosuppression and underpins the growing translational interest in immunometabolism.¹,⁴
References
- Lu Y, et al. Immunometabolism at the intersection of metabolic signaling, cell fate, and systems immunology. Cellular & Molecular Immunology. 2022.
- Li X, et al. Metabolic regulation of the immune system in health and diseases. Signal Transduction and Targeted Therapy. 2024.
- Xu R, et al. Immunometabolism: signaling pathways, homeostasis, and therapeutic targets. MedComm. 2024.
- De Martino M, Rathmell JC, Galluzzi L, Vanpouille-Box C. Cancer cell metabolism and antitumour immunity. Nature Reviews Immunology. 2024.
- Roma EH, Gonçalves JL. Immunometabolism: exploring the nexus of metabolism and immune function in health and disease. Frontiers in Immunology. 2024.
- Liu X, et al. Immunometabolism in rheumatoid arthritis: mechanisms, biomarkers, and the path to precision medicine. Frontiers in Immunology. 2024.
- Zheng F, et al. Editorial: Immunometabolism in autoimmune and autoinflammatory disorders. Frontiers in Immunology. 2023.
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