What is immunometabolism?

Immunometabolism is the study of how cellular metabolic pathways regulate immune cell development, differentiation, and function. These pathways do more than generate energy and biosynthetic precursors. They actively influence signaling pathways, gene expression, and cell fate decisions that shape immune responses.

Immune cells are central components of the immune system, supporting defense, surveillance, and regulation. Their development and maturation depend on coordinated signaling and cytokine cues that ensure precise immune responses. These regulatory systems operate in concert to ensure precise and effective immune function. As these cellular programs change, metabolism is remodeled in parallel to support each functional state.

Different immune cell types adopt distinct metabolic programs depending on activation state and environmental context. These adaptations allow cells to respond rapidly to infection, maintain tissue homeostasis, or resolve inflammation. Understanding these relationships is essential for studying diseases such as cancer, autoimmunity, and chronic inflammation, and for identifying new therapeutic strategies.

Key definitions in immunometabolism

How does metabolism differ across immune cell types?

T cell metabolism: from activation to memory

T cells display distinct metabolic programs at each developmental and activation stage. Naïve T cells rely primarily on oxidative phosphorylation (OXPHOS) and have relatively low biosynthetic demand. Upon activation, effector T cells shift toward aerobic glycolysis and glutaminolysis. This supports rapid proliferation, nucleotide synthesis, cytokine production, and cytotoxic function.

Memory and regulatory T cells favor mitochondrial respiration and FAO-associated pathways. These programs support long-term survival, recall responses, and immunosuppressive function.

Key signaling pathways—including PI3K, Akt, mTOR, MYC, AMPK, and HIF-1α —integrate signals from the T cell receptor, co-stimulation, cytokines, and nutrient availability. These pathways coordinate metabolic remodeling with lineage-specific differentiation and functional output.

T cell metabolism therefore plays a central role in tumor immunity, chronic infection, autoimmunity, immune exhaustion, and responses to immunotherapy.

B cell metabolism

B cell metabolism changes across naïve, activated, germinal center, plasma cell, and memory states. These changes link nutrient use to antibody production and long-term immune protection.

Activation increases glucose uptake and glycolysis to support proliferation and antibody diversification. During germinal center responses, metabolic pathways support class switching and affinity maturation.

Plasma cells depend heavily on mitochondrial metabolism and lipid synthesis to sustain high-rate antibody secretion. In contrast, memory B cells favor oxidative metabolism to support persistence over time.

Signaling nodes, including mTOR, MYC, and PI3K–Akt, coordinate metabolic transitions with proliferation, germinal center reactions, and immunoglobulin production. Dysregulated B cell metabolism contributes to autoimmunity, immunodeficiency, and B cell malignancies.

Macrophage metabolism: Linking inflammation and repair

The function is closely linked to metabolic state and environmental cues. In many experimental models, classically activated M1-like macrophages upregulate glycolysis and show altered TCA cycle activity, supporting inflammatory responses.

Alternatively activated M2-like macrophages are more associated with oxidative phosphorylation and FAO-linked pathways, which support tissue repair and remodeling.

Metabolic intermediates contribute directly to macrophage function. Succinate can accumulate during inflammatory activation and promote HIF-1α signaling and IL-1β production. Itaconate, produced via IRG1/ACOD1, has anti-inflammatory effects and regulates oxidative stress pathways.

These metabolic programs influence cytokine production, phagocytosis, antigen presentation, tissue remodeling, and tumor-associated immune suppression.

Dendritic cell metabolism: Enabling antigen presentation

Dendritic cells (DCs) remodel metabolism in response to activation signals from pattern-recognition receptors, cytokines, and growth factors. Activated DCs typically increase glycolysis to support antigen processing, migration, cytokine production, and T cell priming. Mitochondrial metabolism remains important for subset-specific functions, including survival and cross-presentation. Different DC subsets show distinct metabolic dependencies.

Pathways such as PI3K–Akt, MAPK , NF-κB , and mTOR regulate nutrient uptake, glycolysis, cytokine production, and co-stimulatory molecule expression. These programs enable DCs to coordinate antigen presentation, immune activation, and tolerance.

Natural killer cell metabolism: Supporting cytotoxic function

NK cells (NK) undergo dynamic metabolic reprogramming during activation and acquisition of memory-like features. Resting NK cells maintain relatively low metabolic activity.

Cytokine stimulation, particularly with IL-2 and IL-15 , increases both glycolysis and mitochondrial metabolism. These changes support proliferation, IFN-γ production, and cytotoxic activity.

mTORC1 promotes glycolytic metabolism in activated NK cells, while additional cytokine-driven pathways can act independently of mTOR. Cytokine combinations such as IL-12, IL-15, and IL-18 can induce a metabolically active memory-like state.

Innate lymphoid cell metabolism: Tissue-specific metabolic programs

Innate lymphoid cells (ILCs) show diverse metabolic profiles that depend on subsets and tissue environment. ILC1 populations are often associated with glycolytic programs, while ILC2 and ILC3 subsets integrate lipid metabolism and mitochondrial respiration.

ILCs respond to local factors such as nutrients, oxygen levels, and interleukins . Pathways including mTOR, HIF-1α, and PPAR-γ connect these environmental signals to metabolic and functional responses.

Because ILCs are rare and tissue-resident, high-resolution analyses are often required to distinguish intrinsic metabolic programs from environmental influences.

Neutrophil metabolism: rapid glycolytic responses

Neutrophils are predominantly glycolysis-dependent, allowing rapid antimicrobial responses even in low-oxygen inflammatory tissues. This metabolic profile supports their short-lived but highly effective antimicrobial functions.

Glycolysis fuels chemotaxis, phagocytosis, degranulation, oxidative burst, and neutrophil extracellular trap (NET) formation. Key regulators include HIF-1α and ROS-generating pathways.

Granulocytes contribute to host defense, but dysregulation can drive pathology in sepsis, chronic inflammation, and cancer.

Myeloid-derived suppressor cell: Metabolic immune suppression

Myeloid-derived suppressor cells (MDSCs) use specialized metabolic programs to suppress immune responses. These include altered amino acid metabolism, lipid uptake, lipid oxidation, and ROS production.

Arginase-1 depletes arginine, which is required for T cell function, while iNOS and ROS pathways can impair T cell receptor signaling and proliferation. These mechanisms support immune suppression, tumor immune evasion, and inhibition of anti-tumor T cell activity.

Metabolic profiles vary between monocytic and granulocytic MDSC subsets and depend on tissue context.

Eosinophil metabolism: Lipid and mitochondrial integration

Eosinophils use mitochondrial and lipid-associated metabolic programs to support survival, inflammatory mediator production, and tissue functions in type 2 immunity.

Eosinophils participate in parasite defense, allergic inflammation, asthma, tissue remodeling, and immune regulation. They can integrate mitochondrial metabolism, lipid mediator pathways, and cytokine-driven survival metabolism.

IL-5 is a major eosinophil survival and activation cytokine, and lipid mediators help shape eosinophil recruitment and inflammatory function. Eosinophil metabolism supports granule protein release, cytokine production, lipid mediator generation, and tissue inflammatory responses. Eosinophil immunometabolism is relevant to allergic disease, asthma, helminth infection, and eosinophilic inflammatory disorders.

Tissue-resident myeloid and macrophage subsets: metabolism shaped by location

Tissue location strongly shapes immunometabolism, so macrophages in the lung, liver, adipose tissue, brain, gut, and tumors can have distinct nutrient dependencies and functional states.

These cells adapt to local oxygen levels, lipid availability, microbiota-derived metabolites, cytokines, and tissue-specific growth factors. Examples include tumor-associated macrophages, adipose tissue macrophages, microglia, Kupffer cells, and alveolar macrophages, which may use different combinations of glycolysis, OXPHOS, lipid metabolism, and amino acid metabolism.

Tissue-specific metabolic programs influence inflammation, fibrosis, tissue repair, antigen presentation, immune suppression, and homeostasis.

Why immunometabolism matters in disease

Immunometabolism provides a framework for understanding how immune cells function in health and disease. Metabolic dysregulation contributes to cancer, autoimmunity, chronic inflammation, and infection.

Because metabolism is adaptable and druggable, it offers opportunities for therapeutic intervention. Targeting metabolic pathways can help modulate immune responses in immunotherapy, inflammatory disease, and tissue repair.

References

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