Tissue-Specific Metabolic Reprogramming in Innate Lymphoid Cells and Its Impact on Disease

Abstract

Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets—ILC1, ILC2, and ILC3—are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.

INTRODUCTION

Innate lymphoid cells (ILCs) are essential regulators of tissue immunity, serving as important intermediaries between the innate and adaptive immune systems (1). Unlike T cells, which have Ag-specific receptors, ILCs lack these receptors but are highly responsive to cytokine signals and environmental cues, enabling them to act swiftly in response to tissue damage or infection (2). Predominantly resident in mucosal tissues such as the lung, gut, and skin, ILCs occupy specialized niches where they play crucial roles in maintaining immune homeostasis and defending against pathogens. These cells are broadly classified into 3 main subsets: ILC1, ILC2, and ILC3. ILC1s resemble Th1 cells in their ability to produce IFN-γ, contributing to antiviral and antitumor immunity. ILC2s, similar to Th2 cells, produce IL-5 and IL-13, which are pivotal in orchestrating type 2 immune responses and are particularly involved in allergic diseases. ILC3s, aligned with Th17 cells, produce IL-17 and IL-22 and are essential for mucosal immunity and gut homeostasis (3).

While ILCs are traditionally studied for their roles in cytokine production, recent research has revealed their dynamic metabolic reprogramming, which is integral to their activation and function. ILCs utilize metabolic pathways such as glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO) to meet the energetic and biosynthetic demands of their specific tissue environments (4). Given their tissue residency, ILCs are uniquely positioned to sense and respond to metabolites derived from their surrounding environments, further underscoring the importance of metabolic states in modulating their immune functions. Understanding the intersection of metabolism and ILC activity opens new avenues for therapeutic strategies targeting immune-related diseases and metabolic disorders.

METABOLIC PATHWAYS IN ILCs

Immune cells, including ILCs, finely regulate their metabolic processes to meet the energetic and biosynthetic requirements essential for their immunological functions. Three primary metabolic pathways—glycolysis, OXPHOS, and FAO— play critical roles in sustaining immune activities. Glycolysis is often associated with rapid ATP generation, particularly during activation, while mitochondrial respiration through OXPHOS supports the heightened energy demands of proliferation and effector responses. Additionally, lipid metabolism, including FAO, serves as an energy source under certain activation states or environmental conditions (5). Recent evidence indicates that ILCs exhibit distinct metabolic profiles in response to diverse stimuli, enabling them to adapt dynamically to their surroundings (Table 1). Understanding these metabolic pathways is crucial for comprehending ILC function and regulation. This section explores the metabolic pathways influencing ILC phenotypes.

Table 1. Metabolic regulators and their impact on ILC function.

Subset	Metabolic pathway	Metabolic alteration	Regulators	Function	References
ILC1/NK cell	Glycolysis	Glycolysis↑	mTORC	IFN-γ, granzyme B production, proliferation during NK cell development	(6,7)
		Glycolysis↓	PD-1	Diminished proliferation and anti-tumor effect	(10)
	OXPHOS	OXPHOS↑	SREBP	Cell growth and proliferation, effector cytokine production (IFN-γ, granzyme B)	(11)
	FA metabolism	FAO↑	PPARα/δ	Lipid accumulation, inhibition of mTOR-mediated glycolysis, diminished cytotoxicity	(14)
ILC2	Glycolysis	Glycolysis↑	Arg1	Facilitation of allergen-induced proliferation and type 2 response	(17)
			mTOR	Production of IL-5 and IL-13 upon activation	(18)
			HIF-1α	Reduction of type 2 cytokine production and maintenance of ILC2s	(19,20)
		Glycolysis↓	PD-1	Inhibition of type 2 cytokine productions, reduced proliferation	(16)
			CD226	Type 2 cytokine production, proliferation, maintaining GATA3 expression	(21)
			VHL, TfR1	Development and functionality of ILC2s by inhibiting HIF-1α-mediated glycolysis	(19,20)
	OXPHOS	OXPHOS↑	LKB1	Maintenance of functional mitochondria and prevents exhaustion	(22,23)
			ORAI channel	Maintenance of mitochondrial homeostasis and decrease cellular oxidative stress	(24)
		OXPHOS↓	DRD1	Reduction of ATP synthesis and decreased type 2 cytokine production	(25)
	FA metabolism	FAO↑	DGAT1, PPAR-γ	Lipid droplet formation which fuels energy for proliferation and cytokine production, prevention of lipotoxicity	(28)
			ATG5	Enhancement of effector function upon activation	(30)
		FAO↓	RXRγ	Reduction of cellular neutral lipids, reduced ILC2 response	(29)
ILC3	Glycolysis	Glycolysis↑	mTOR, HIF-1α	Development, proliferation, RORγt expression, and secretion of effector cytokine (IL-17A, IL-22)	(31)
			Tox2	Protein translation and gut maintenance of ILC3s	(32)
	OXPHOS	OXPHOS↑	TFAM	Maintenance of gut ILC3s, production of IL-22	(34,35)
	FA metabolism	FAS↑	ACC1	IL-22 production in the context of bacterial infection	(37)
			c-Maf	Prevention of conversion to ILC1s	(38)
		FAO↓	PD-1	Glycolytic switch and IL-22 production of LTi cells	(39)

TfR1, transferrin receptor 1; DRD1, dopamine receptor D1; ACC1, acetyl-CoA carboxylase 1; FAS, fatty acid synthesis.

ILC1 METABOLISM

Glycolysis

Glycolysis is a critical metabolic pathway supporting the activation and functionality of ILC1s, including NK cells. The mTOR complex (mTORC) plays a central role in glycolytic reprogramming, regulating the development, proliferation, and activation of ILC1s. Donnelly et al. (6) demonstrated that mTORC1-mediated glycolysis is indispensable for NK cell production of IFN-γ and granzyme B upon stimulation with IL-2 and IL-12. Furthermore, enhanced mTOR signaling was shown to drive glycolysis during NK cell proliferation and activation in response to inflammation (7). Transcriptional analyses further revealed that non-cytotoxic ILC1s also exhibit an upregulated mTOR pathway, underscoring the relevance of glycolysis across ILC1s (8).

Another example of glycolysis-dependent functionality comes from Mycobacterium tuberculosis infection models, where glucose supplementation promoted differentiation of IL-18Rα⁺ lung ILC precursor into ILC1-like cells and enhanced IFN-γ production. Conversely, treatment with 2-deoxyglucose (2-DG) inhibited glycolysis, leading to impaired differentiation and effector function, further emphasizing the critical role of glucose metabolism in ILC1 activation (9). Interestingly, glycolysis in ILC1s can also be negatively regulated under specific conditions. For instance, PD-1 signaling in T-bet⁺ NK1.1⁻ ILC1s within the tumor microenvironment was shown to suppress the mTOR pathway, diminishing glycolysis while promoting fatty acid (FA) uptake. This metabolic shift led to reduced proliferation and functional impairment of T-bet⁺ NK1.1⁻ ILC1s, demonstrating how glycolysis can be modulated by environmental and signaling cues such as lactate-induced PD-1 expression (10). Collectively, these findings illustrate that glycolysis serves as a foundational metabolic program for ILC1 activation, proliferation, and effector functions, with mTOR and PD-1 pathways playing regulatory roles (Fig. 1A).

Figure 1. Metabolic regulators governing ILC metabolism.

(A) mTOR signaling drives glycolysis in NK cells, while PD-1 signaling in T-bet⁺ NK1.1⁻ ILC1s within the tumor microenvironment suppresses glycolysis and promotes fatty acid uptake. SREBP supports OXPHOS, whereas PPAR-α/PPAR-δ activation impairs glycolysis and induces lipid accumulation. (B) In ILC2s, Arg1, mTOR, and HIF-1α promote glycolysis, while PD-1 and CD226 signaling inhibit it. VHL and iron metabolism suppress HIF-1α-mediated glycolysis. LKB1 supports glycolysis and OXPHOS by inhibiting PD-1 expression. Ca²⁺-ORAI signaling sustains OXPHOS, whereas dopamine signaling negatively regulates it. DGAT1/PPAR-γ and RXRγ differentially regulate lipid metabolism in pulmonary and intestinal ILC2s. ATG5 prevents glycolytic reprogramming while maintaining OXPHOS. (C) In ILC3s, HIF-1α modulates glycolysis via mTOR and hypoxia-induced pathways, upregulating Tox2 and Hk2. TFAM, regulated by NPM1 and p65, is essential for OXPHOS, while Bcl-2 reduces mROS in LTi-like ILC3s. ACC1 drives lipid synthesis, and PD-1 signaling suppresses FAO, promoting glycolysis in LTi cells. Solid lines represent signaling pathways that promote or induce specific metabolic processes, whereas dashed lines denote pathways that inhibit or suppress these processes.

ACC1, acetyl-CoA carboxylase 1; mROS, mitochondrial ROS; LD, lipid droplet; DRD1, dopamine receptor D1.

OXPHOS

Although glycolysis provides rapid ATP for ILC1 activation, OXPHOS plays a complementary role in meeting the increased energy demands of activated cells. Research has shown that activated NK cells exhibit enhanced glycolysis and OXPHOS, with both pathways being essential for cytokine production and cytotoxicity. Assmann et al. (11) demonstrated that sterol regulatory element-binding protein (SREBP) drives simultaneous glycolysis and OXPHOS upregulation in NK cells, facilitating optimal IFN-γ and granzyme B production. Impairment of SREBP led to reduced cell growth and proliferation due to compromised energy metabolism (11). Similarly, Wang et al. (12) reported that NK cells stimulated by anti-CD16 Abs or NKG2D ligands displayed increased OXPHOS alongside glycolysis, with both pathways proving critical for IFN-γ secretion. These results highlight the cooperative function of glycolysis and OXPHOS in sustaining NK cell activity during immune responses (12).

While fewer studies have explored OXPHOS in non-cytotoxic ILC1s, evidence suggests that distinct mitochondrial metabolism exists within specific subsets. Salome et al. (13) identified unconventional human CD56⁺ ILC1-like cells with higher nutrient uptake and more efficient mitochondrial activity compared to conventional ILC1s. This finding implies that mitochondrial respiration may play a unique role in supporting the cytotoxic functions of certain ILC1 subsets (Fig. 1A) (13).

FA metabolism

FA metabolism in ILC1s, particularly NK cells, has been shown to influence immune function under specific conditions. Michelet et al. (14) revealed that lipid accumulation in NK cells, often observed in obesity, impairs mTOR signaling, suppressing glycolysis and reducing anti-tumor responses. Activation of peroxisome proliferator-activated receptor (PPAR)-α or PPAR-δ pathways led to lipid accumulation, further inhibiting NK cell cytokine production via mTOR pathway suppression (14). Similarly, Kobayashi et al. (15) reported that elevated intracellular neutral lipids in NK cells negatively correlated with mTOR activity. Palmitate administration significantly inhibited glucose metabolism and cytokine secretion, underscoring the inhibitory role of excessive lipids in NK cell functionality (15).

While these findings largely focus on NK cells, they suggest that lipid metabolism may also influence non-cytotoxic ILC1 subsets under specific environmental conditions, potentially contributing to functional regulation. The interplay between FA metabolism, glycolysis, and OXPHOS highlights the complexity of metabolic regulation in ILC1s, offering insight into how environmental and intrinsic factors shape their immune responses (Fig. 1A).

ILC2 METABOLISM

Glycolysis

Glycolysis is critical for ILC2 activation, proliferation, and cytokine production, with its regulation varying depending on cellular context. Helou et al. (16) demonstrated that PD-1 signaling suppresses glycolytic activity in pulmonary ILC2s, thereby promoting apoptosis and dampening type 2 cytokines, such as IL-5, IL-9, and IL-13. PD-1 blockade restored glucose metabolism, shifted the balance toward aerobic glycolysis, increased GATA3 expression, and reduced apoptosis. However, inhibition of glucose utilization with 2-DG abrogated these effects, underscoring the indispensable role of glucose metabolism in ILC2 survival and activation (16). Arginase-1 (Arg1), in contrast, promotes glycolysis to support allergen-driven ILC2 proliferation and cytokine production. Pharmacological inhibition of Arg1 reduced glycolytic capacity and attenuated airway hyperresponsiveness (AHR), highlighting glycolysis as a metabolic checkpoint in allergen-induced responses (17). Similarly, Surace et al. (18) found that glycolysis, along with mTOR signaling, is necessary for IL-5 and IL-13 production upon IL-33 stimulation.

However, excessive glycolysis can be detrimental. Li et al. (19) showed that von Hippel-Lindau (VHL) protein, an E3 ubiquitin ligase, suppresses hypoxia-inducible factor (HIF)-1α-mediated glycolysis in ILC2s. Loss of VHL increased glycolysis but reduced type 2 cytokine production and survival, indicating a delicate balance in glycolytic regulation (19). Transferrin receptor 1 (TfR1)-mediated iron metabolism also constrains HIF-1α-mediated glycolysis in ILC2s. Iron deprivation enhanced glycolytic flux while suppressing OXPHOS, impairing ILC2 function (20). Interestingly, CD226 signaling inhibits glycolysis to maintain functional ILC2 responses. Blockade of CD226 led to metabolic shifts favoring glycolysis at the expense of FA metabolism, impairing cytokine production (21). These findings highlight the context-dependent roles of glycolysis and suggest therapeutic potential in fine-tuning its pathways to modulate ILC2-driven diseases (Fig. 1B).

OXPHOS

Mitochondrial metabolism, particularly OXPHOS, is integral to ILC2 function. Sun et al. (22) identified the tumor suppressor liver kinase B1 (LKB1) as essential for maintaining mitochondrial integrity and type 2 cytokine production in adipose tissue (AT) ILC2s. Obesity-induced LKB1 deficiency triggered mitochondrial dysfunction via ROS-nuclear factor of activated T-cells 2 signaling, leading to PD-1 upregulation and mitophagy in ILC2s. This process generated dysfunctional mitochondria, inhibited OXPHOS, impaired type 2 cytokine production in ILC2s, and ultimately exacerbated insulin resistance (22). Similarly, Niu et al. (23) reported that LKB1 deficiency impaired both glycolysis and OXPHOS, promoting ILC2 exhaustion.

Calcium signaling also governs OXPHOS in ILC2s. Howard et al. (24) demonstrated that the Ca²⁺ release-activated Ca²⁺ (CRAC) channels Orai1 and Orai2 sustain OXPHOS and FA uptake in pulmonary ILC2s. Orai channel inhibition impaired mitochondrial function and increased ROS production without a compensatory glycolytic shift, highlighting the reliance of ILC2s on functional mitochondria (24).

Moreover, neurotransmitter signaling modulates mitochondrial metabolism. Dopamine receptor D1 (DRD1) signaling suppressed OXPHOS in lung ILC2s by reducing the oxygen consumption rate (OCR) and ATP synthesis. This suppression inhibited ILC2 proliferation and cytokine production, alleviating HDM-induced airway inflammation (25). Together, these findings emphasize the centrality of OXPHOS in maintaining ILC2 metabolic fitness and immune responses (Fig. 1B).

FA metabolism

FA-metabolism is a cornerstone of ILC2 biology, providing both energy and signaling molecules. Wilhelm et al. (26) first demonstrated that ILC2s have higher FA uptake than other ILC subsets, with lipid metabolism essential for their proliferation and cytokine production during helminth infection. Blocking lipid metabolism with etomoxir significantly impaired these processes, emphasizing the importance of FA metabolism in ILC2 responses (26). Additionally, transcriptomic analysis revealed that ILC2s express lipid metabolism-related genes at higher levels than other ILC subsets, suggesting the importance of FA metabolism in ILC2 biology (27).

Transcriptional and metabolic regulators modulate FA metabolism in ILC2s. PPAR-γ and diacylglycerol O-acyltransferase 1 (DGAT1) promote lipid droplet formation in IL-33-stimulated pulmonary ILC2s, preventing lipotoxicity and providing energy for cytokine production (28). Conversely, retinoid X receptor gamma (RXRγ) suppresses ILC2 responses in the small intestine by promoting cholesterol efflux, reducing intracellular lipid accumulation, and curbing type 2 responses during helminth infection. Moreover, neutral lipids may serve as metabolic fuels for ILC2s, with RXRγ deficiency resulting in increased neutral lipid levels and augmented ILC2 responses during helminth infection (29).

Autophagy-mediated lipolysis also plays a pivotal role in FA metabolism by sustaining FAO and supporting ILC2 function. The loss of Atg5, a key autophagy-related gene, disrupts FAO in ILC2s, forcing a metabolic shift toward glycolysis and increasing apoptosis. This dysregulation impaired IL-33-induced AHR, underscoring the role of autophagy in maintaining FA metabolism and ILC2 survival (30). Key regulators of FA metabolism in ILC2s include PPAR-γ, which promotes FAO crucial for ILC2 activation and survival, and DGAT1, which facilitates energy storage through triglyceride synthesis (28). RXRγ governs the expression of lipid metabolism-related genes (29), while Atg5 sustains FAO through autophagy-mediated lipolysis, preventing glycolytic shifts that compromise cell viability (30). These pathways collectively underscore the importance of lipid metabolism in maintaining ILC2 function and present promising targets for therapeutic intervention.

The metabolic regulation of ILC2s is crucial for their function, encompassing glycolysis, OXPHOS, and FA metabolism. These pathways not only supply energy and mitochondrial function but also regulate immune responses. The integration of these metabolic processes underscores the intricate interplay that governs ILC2 behavior, highlighting the therapeutic potential of targeting these pathways in disease contexts (Fig. 1B).

ILC3 METABOLISM

Glycolysis

Aerobic glycolysis is essential for providing energy and biosynthetic intermediates for immune cells, including ILC3s. In ILC3s, glycolysis regulates effector function and maintenance, similar to its role in Th17 cells. The mTOR-HIF-1α axis plays a crucial role in the glycolytic reprogramming of ILC3s. Di Luccia et al. (31) showed that upon activation by IL-1β and IL-23, ILC3s enhance glycolysis through mTORC1, supporting RORγt expression and the secretion of IL-17A and IL-22, which promotes ILC3 proliferation. Furthermore, HIF-1α activation is necessary for gut homeostasis and immune responses. Das et al. (32) demonstrated that HIF-1α induces Tox2 and its downstream target, hexokinase-2 (Hk2), in gut ILC3s. Hk2, a key enzyme in glycolysis (33), is critical for the metabolic adaptation of gut ILC3s to hypoxic conditions often encountered during tissue injury or bacterial infection (Fig. 1C).

OXPHOS

Mitochondrial OXPHOS is vital for ILC3 homeostasis and function. Mitochondrial transcription factor A (TFAM), which regulates mitochondrial DNA and OXPHOS, is crucial for ILC3 maintenance. TFAM-deficient mice show impaired ILC3 function, highlighting the importance of mitochondrial metabolism for ILC3 survival and cytokine production (34). Zhao et al. (35) further emphasized that TFAM, regulated by nucleophosmin 1 (NPM1) and p65, protects against IBD by supporting mitochondrial function. NPM1 deficiency impairs the electron transport chain, reducing OCR value and IL-22 production, exacerbating Dextran sulfate sodium (DSS)-induced colitis (35). Additionally, King et al. showed that IL-22 production in CCR6⁺ LTi-like ILC3s depends on OXPHOS. However, they also found that excessive mitochondrial respiration, in the absence of the anti-apoptotic protein Bcl-2, generates ROS that impair LTi-like ILC3 survival (36). Thus, while OXPHOS is critical for ILC3 function, it is important to balance mitochondrial activity to prevent stress (Fig. 1C).

FA metabolism

FA metabolism, particularly de novo lipid synthesis, plays a key role in ILC3 function. Acetyl-CoA carboxylase 1 (ACC1), responsible for FA synthesis, is essential for IL-22 production in ILC3s during Citrobacter rodentium infection or IL-1β/IL-23 stimulation (37). Moreover, c-Maf, which regulates cholesterol biosynthesis, is necessary for maintaining ILC3 identity and preventing conversion to ILC1s. Lipid intermediates from cholesterol biosynthesis also act as ligands for RORγt, further linking lipid metabolism to ILC3 function and plasticity (38). On the other hand, FAO has been shown to inhibit LTi cell activation. In DSS-induced colitis, upregulated PD-1 signaling inhibits FAO in LTi cells, shifting metabolism toward glycolysis and promoting IL-22 production. In contrast, PD-1 deficiency exacerbates colitis by reducing IL-22 production, suggesting that FAO inhibition may benefit LTi cells in inflammatory contexts (39). This highlights the metabolic flexibility of ILC3s, which can shift between glycolysis and FA metabolism depending on the environmental cues.

In summary, ILC3s utilize a complex interplay of glycolysis, OXPHOS, and FA metabolism to support their diverse functions in homeostasis and immunity. The mTORC1-HIF-1α axis regulates glycolysis, while factors like TFAM maintain OXPHOS, and lipid pathways influence ILC3 identity and plasticity. This metabolic flexibility allows ILC3s to adapt to the unique tissue microenvironment, enabling efficient cytokine production and cellular maintenance while offering potential targets for therapeutic interventions (Fig. 1C).

METABOLIC CROSSTALK BETWEEN ILCs AND TISSUE-SPECIFIC ENVIRONMENTS

Given that each tissue in the body has its own distinct metabolic environment, it is plausible that tissue-specific metabolites may regulate ILC function, differentiation, and homeostasis. Furthermore, ILC subsets are distributed differently across tissues. ILC2s are predominantly found in the lung, skin, and adipose tissue, while ILC3s dominate in the gut (40). These variations in ILC composition may be influenced by tissue-specific metabolites, which could further regulate the functions of each subset. The metabolic landscape of tissues can profoundly impact ILC activity and contribute to disease progression. In this context, examining the role of tissue-specific metabolites in regulating ILC functions will provide important insights into how ILCs contribute to disease pathophysiology and help identify potential therapeutic targets. In the following sections, we explore how different tissues, such as the lung, gut, and skin, shape the metabolic environment to influence ILC activity and their involvement in various diseases.

Gut: microbiota, metabolism, and ILC crosstalk

The intestine, as a digestive organ, harbors immune cells that interact with a multitude of nutrients and metabolites. It is also home to a diverse range of commensal microbiota that secretes metabolites such as SCFAs, vitamins, and amino acids (AAs), all of which influence immune responses within the mucosal tissue (41,42,43,44). These metabolites can regulate the immune functions of ILCs in the gut, influencing both homeostasis and disease progression (Fig. 2A).

Figure 2. Tissue-derived metabolites regulate the functions of ILCs.

(A) Intestinal SCFAs, Trp, and RA enhance IL-22 production in ILC3s via Ffar- or AhR-mediated signaling. SCFAs and RA suppress ILC2 function, maintaining the ILC2/ILC3 balance in the intestine. (B) Lipid metabolites regulate ILC2 activity, with LTs boosting proliferation and cytokine production. Prostaglandins have opposing effects: PGD₂ activates ILC2s, while PGI₂ and PGE₂ suppress them. In contrast, PGI₂ and PGE₂ enhance ILC3 cytokine production. Vitamins A (RA) and D promote IL-10 production in ILC2s, and vitamin C boosts lung NK cell activity. AAs activate ILC2s via LAT transporters, supporting their function. (C) SCFAs in skin regulate type 2 and type 17 cytokines, influencing atopic dermatitis and psoriasis. UVB-induced vitamin D synthesis in the epidermis suppresses ILC2 and ILC3 activity, reducing disease severity. (D) SCFAs and RA induce Pparγ and Ucp expression in adipocytes, enhancing oxidative metabolism. SCFA-GPR43 signaling and vitamin D stimulate M2 macrophage polarization and eosinophil recruitment. AT ILC2s amplify metabolite-driven oxidative metabolism.

Short-chain fatty acids (SCFAs)

SCFAs, including butyrate, acetate, and propionate, play significant roles in regulating intestinal ILCs, particularly ILC3s (Fig. 2A). Butyrate, a microbiota-derived SCFA, has been shown to activate the aryl hydrocarbon receptor (AhR) and HIF-1α via STAT3 and mTOR signaling pathways in lamina propria ILC3s. This activation induces IL-22 production, which helps protect against C. rodentium infection and alleviates colitis (45). However, butyrate exerts different effects in the terminal ileum Peyer’s patch ILC3s, as observed by Kim et al., who found that butyrate impairs IL-22 production and reduces NKp46⁺ ILC3 frequency. This effect was reversed by inhibiting G-protein-coupled receptor (GPR) 109a signaling (46), suggesting that tissue-specific ILC residency influences the response to butyrate.

In addition to butyrate, other SCFAs, such as acetate and propionate, modulate ILC3s in the colon. Chun et al. (47) demonstrated that ILC3s express the free fatty acid receptor (Ffar) 2, which senses SCFAs. Feeding SCFA-rich diets enhanced IL-22 secretion and ILC3 proliferation. Conversely, Ffar2 knockout led to reduced IL-22⁺ ILC3s and impaired pathogen clearance during C. rodentium infection (47). Moreover, SCFAs also influence ILC1s and ILC2s, with acetate, propionate, and butyrate promoting ILC3 expansion, while butyrate increased ILC1 numbers and propionate reduced ILC2s. Depletion of Ffar2 resulted in a reduction of all ILC subsets under both homeostatic and C. rodentium infection conditions (48), highlighting the importance of SCFAs in modulating ILC responses.

Vitamins

Vitamins, particularly vitamin A (retinoic acid, RA) and vitamin D, are critical in regulating ILC functions in the gut. RA has been shown to enhance IL-22 secretion from ILC3s while suppressing IL-17A, thereby offering resistance against colitis and C. rodentium infection (49). Spencer et al. found that RA regulates both ILC3s and ILC2s, and its deficiency reduces ILC3 numbers while expanding ILC2s (50). Thus, RA helps maintain the balance between these subsets and supports intestinal barrier integrity. In the context of bacterial infections, vitamin A deficiency impairs IL-22 production and increases susceptibility to infections, whereas it may protect against helminth infections through ILC2-mediated type 2 responses.

Vitamin D also plays a key role in gut immunity. Deficiency in vitamin D is associated with IBD, such as Crohn’s disease and ulcerative colitis, and supplementation has been shown to reduce disease severity (51,52). Konya et al. (53) demonstrated that vitamin D’s active form, 1,25-dihydroxyvitamin D3 (1,25D), inhibits IL-23-mediated signaling in human tonsillar and gut ILC3s without affecting proliferation or viability. Instead, it reduces IL-23 receptor expression, RORγt, AhR, and type 17 cytokines, particularly selectively inhibiting IL-22 and GM-CSF secretion from NKp44⁺ ILC3s (53). These findings suggest that both vitamins A and D contribute to maintaining intestinal homeostasis by promoting IL-22 production from ILC3s.

AAs

AAs, particularly tryptophan (Trp), have been implicated in regulating ILC functions, although direct evidence linking Trp to intestinal ILC regulation is limited. Trp deficiency has been shown to alter the gut microbiota and influence Treg subsets in an AhR-dependent manner (54). AhR, which is highly expressed in ILC3s, may play a role in regulating ILC3s in response to Trp metabolites. Zelante et al. (55) found that Lactobacillus in the intestine degrades Trp, producing metabolites like indole-3-aldehyde, which activates AhR to induce IL-22 production from NKp46⁺ ILC3s. This Trp-AhR axis promotes IL-22 secretion, offering protection against fungal infections and colitis. These studies highlight the importance of maintaining balanced intestinal metabolites to regulate ILC3-mediated immunity and protect against infections and inflammation.

Lungs: breathing life into ILCs with metabolic cues

Although the pulmonary tract is easily considered an irrelevant organ with immuno-metabolism, several studies suggested that metabolomic changes exist in respiratory diseases. Multi-omics analysis of COVID-19 (56), puenomia (57), bronchiolitis (58), and asthma (59) have shown that metabolite profiles differ between healthy individuals and those with disease. These changes in tissue metabolites and their utilization may serve as regulatory factors for tissue-resident ILCs (Fig. 2B).

Lipid meditators

Lipid mediators, such as leukotrienes (LTs), play a significant role in regulating ILC functions and modulating airway inflammation. ILC2s express receptors for cysteinyl leukotrienes (CysLTR1 and CysLTR2) and leukotriene B₄ (LTB4R1), which mediate their activation (60,61,62). LTD₄, for example, induces calcium influx and enhances IL-5 and IL-13 production in ILC2s (60). In vivo studies confirm that LTC₄, in combination with IL-33, significantly increases IL-5 and IL-13 production, as well as eosinophil recruitment during allergic inflammation (61). Importantly, Cysltr1^−/− mice show diminished responses to LTC₄, confirming the importance of the CysLTR1-LTC₄ axis in lung inflammation (62). Additionally, LTs contribute to the pathogenesis of idiopathic pulmonary fibrosis, where their inhibition reduces inflammatory cytokine production and improves fibrosis in preclinical models (63,64).

Prostaglandin D₂ (PGD₂) enhances ILC2 activity by binding to CRTH2, which increases IL-5 and IL-13 secretion, promoting allergic inflammation (65). In contrast, PGI₂ and PGE₂ have inhibitory effects on ILC2s. PGI₂ suppresses ILC2 cytokine production in response to allergens, and its receptor-deficient mice show worsened disease symptoms. Similarly, PGE₂ treatment reduces IL-13 production by ILC2s but promotes IL-22 production by ILC3s, with distinct roles in modulating airway inflammation and injury in different contexts (66).

SCFAs

SCFAs are metabolites derived from the intestine that have been implicated in modulating airway immunity, a phenomenon referred to as the gut-lung axis (67,68). Studies by Jiang et al. (69,70) demonstrated that a high-fiber diet suppresses chronic obstructive pulmonary disease by butyrate-mediated inhibition of ILC2s. This diet increases intestinal SCFA levels, and butyrate specifically reduce cytokine production and activation of ILC2s (69,70). In addition, the influence of intestinal SCFAs on lung ILC2 regulation is further supported by the work of Lewis et al. (71), which showed that a high-fiber diet increases SCFA levels in both the colon and lung. In this context, butyrate significantly suppresses ILC2 function and alleviates the severity of allergic asthma (70). Together, these studies highlight the capacity of microbiota-derived SCFAs to modulate ILC functions in both the intestine and the lung, underscoring the close relationship between these 2 organs.

Vitamins

Vitamin A modulates ILC2 activity by inducing IL-10 secretion in human ILC2s. Morita et al. (72) showed that RA treatment increased IL-10 production in a dose-dependent manner. Furthermore, ALDH1A1, a gene involved in RA synthesis, was upregulated in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). IL-13 production from ILC2s further promoted RA synthesis, which boosted IL-10 production in CRSwNP (72). Clinical studies have suggested that vitamin D also plays a significant role in asthma severity and lung function, with supplementation shown to alleviate asthma exacerbation (73,74). Vitamin D₃ supplementation in asthmatic adults reduces asthma manifestations and increases IL-10 levels, with enhanced expression of GATA3 in ILC2s. Interestingly, vitamin D₃-treated ILC2s show increased Blimp-1 expression and IL-10 secretion but reduced production of type 2 cytokines (75). These findings suggest that vitamin D inhibits the canonical stimulatory pathways of ILC2s, promoting alternative features such as IL-10 production. Additionally, Golebski et al. (76) observed that vitamin D inhibits the conversion of human blood ILC2s to ILC3s in vitro, indicating that vitamin D directly regulates ILC2 function and influences the ILC2-ILC3 balance. Vitamin C has a protective role in airway viral infections. Oral administration of vitamin C reduced H1N1 virus-induced pneumonia (77), suggesting its potential to regulate airway immunity. Heuser and Vojdani (78) demonstrated that vitamin C enhanced NK cell activity, which was associated with protein kinase C signaling. Since NK cells are involved in immune surveillance, vitamin C may enhance NK cell function, attenuating pulmonary viral infections.

AAs

Recent studies have highlighted the importance of AAs in regulating lung ILC2 functions. Metabolomic analysis of feces from helminth-infected mice revealed that many essential AAs were elevated alongside activated ILC2s. Moreover, a low-protein diet inhibited ILC2 proliferation and cytokine production during infection, emphasizing the role AA availability in ILC2 activity (79). Both intestinal and lung ILC2s express Slc7a5 (LAT1) and Slc7a8 (LAT2), key AA transporters. Deletion of Slc7a5 or Slc7a8 from ILC2s impaired their proliferation and cytokine production (79). Panda et al. demonstrated that Il7ra^creSlc7a8^fl/fl mice showed reduced ILC2 numbers and IL-5/13 production, which impacted their ability to resist Heligmosomoides polygyrus infection and house dust mite-induced airway inflammation (80). These findings underscore the critical role of AA utilization in ILC2 homeostasis and function.

Skin: metabolic signals in epidermal immunity

ILCs are crucial for maintaining skin immune homeostasis and regulating skin responses to both environmental and metabolic challenges. These immune cells interact with various metabolic signals that influence their differentiation, activation, and overall immune function in the skin. Given the skin’s role as a barrier and immune sentinel, its metabolic environment significantly shapes immune responses, especially in conditions such as atopic dermatitis (AD), psoriasis, and other inflammatory skin diseases (Fig. 2C).

SCFAs

SCFAs influence systemic immunity, including skin immunity. Trompette et al. (81) highlighted the role of SCFAs in regulating keratinocyte metabolism and differentiation, ultimately strengthening skin barrier integrity. Moreover, Xiao et al. (82) demonstrated the capacity of SCFAs to modify gut microbiota, promoting systemic benefits that extend to skin health. In the context of inflammatory skin diseases, SCFAs may help balance immune responses by controlling ILCs. Although there is no direct evidence of the regulatory roles of SCFA in skin ILCs, their role in reducing ILC2 activity along with mitigating pro-inflammatory cytokine environments underscores their therapeutic potential for conditions like AD (71). Moreover, Chen et al. (83) demonstrated that SCFAs reduce IL-17 production, suggesting potential benefits for managing psoriasis and other type 1 immune-driven conditions. The ability of SCFAs to influence both local and systemic immune pathways highlights their promise as modulators of skin immunity and potential adjuncts in treating inflammatory skin disorders.

Vitamins

Vitamin D, primarily synthesized in the skin upon ultraviolet B (UVB) exposure, plays a crucial role in modulating immune responses in the epidermis (84,85). While direct links between vitamin D and ILCs in skin immunity are not fully established, several studies support its regulatory effects on skin-resident ILC populations. In the AD model, characterized by type 2 inflammation, ILC2s are abundant and contribute to disease progression by producing IL-5 and IL-13, which exacerbate inflammation and impair skin barrier function. Vitamin D₃, known to reduce type 2 cytokine production in models of airway and intestinal inflammation, likely exerts similar effects on the skin (86,87,88). These findings suggest that vitamin D-mediated control of ILC2 activity could underlie its protective role in AD, promoting an anti-inflammatory environment. In psoriasis, vitamin D acts by suppressing IL-17 production by ILC3s (53). Konya et al. (53) demonstrated that 1,25D reduces IL-23 receptor expression and cytokine secretion, including IL-22, IL-17F, and GM-CSF, in ILC3s. Furthermore, vitamin D may inhibit the conversion of ILC2s into ILC3s, thereby limiting IL-17-driven inflammation (76). The therapeutic efficacy of vitamin D in managing psoriasis, supported by numerous clinical observations (89,90), underscores its role in modulating ILC3s and associated inflammatory pathways.

ILCs play a key role in maintaining skin immune homeostasis by interacting with various metabolic signals. While more research is needed to clarify the regulatory mechanisms of vitamins and other metabolites on ILCs, their interplay suggests a promising avenue for treating skin diseases and enhancing skin health. Understanding how metabolic and immune processes converge in the skin will provide crucial insights into future therapeutic strategies.

AT: a focus on key metabolites

AT plays a central role in maintaining metabolic homeostasis and is influenced by various metabolic signals. Recent research has highlighted the importance of ILC2s in the regulation of adiposity, energy expenditure, and inflammation (91). AT ILCs respond to both immune and metabolic cues, influencing the tissue’s response to nutritional changes, obesity, and metabolic disorders. Understanding the metabolic regulation of these cells provides valuable insights into the intersection of immune function and metabolism (Fig. 2D).

SCFAs

SCFAs have been shown to activate key signaling pathways in adipocytes and immune cells, promoting thermogenesis and improving insulin sensitivity—critical aspects of obesity prevention and management. One of the key mechanisms by which SCFAs exert their beneficial effects is through the modulation of peroxisome PPAR-γ signaling in AT, which shifts lipid metabolism from storage to utilization. This process increases oxidative metabolism through mitochondrial uncoupling protein (UCP) 2 and AMP-activated protein kinase activation. SCFA supplementation has been shown to prevent high-fat diet-induced metabolic issues in mice, but this effect is lost in mice with adipose-specific PPAR-γ disruption, highlighting the crucial role of PPAR-γ in SCFA-induced metabolic improvements (92).

In addition to their metabolic effects, SCFAs influence immune cell activity within AT, including ILC2s. ILC2s are essential for maintaining tissue homeostasis and regulating local inflammation, both of which are important for metabolic health. ILC2s contribute to tissue remodeling and “browning” of white adipose tissue, which increases energy expenditure and improves insulin sensitivity (91). Given their role in regulating inflammation and tissue homeostasis, ILC2s may be modulated by SCFAs through several mechanisms, including cytokine production, immune cell recruitment, and activation. Furthermore, SCFAs are known to influence macrophage polarization in AT, with butyrate sensing receptor (GPR43), in particular, promoting the M2 macrophage phenotype, which helps resolve inflammation and maintain tissue homeostasis (93). This process may synergize with ILC2 function, as M2 macrophages and ILC2s work together to mitigate the chronic inflammation that characterizes obesity (94,95). While direct evidence linking SCFAs to ILC2 activation is still limited, their ability to influence immune cells like macrophages suggests that SCFAs could enhance ILC2 function, contributing to improved metabolic regulation.

Vitamins

Vitamins play a pivotal role in modulating AT biology, with emerging evidence suggesting their impact on the activity and function of ILCs. Vitamin A, primarily as RA, promotes the differentiation of adipocyte precursors into beige adipocytes, which exhibit thermogenic properties similar to brown adipocytes. This process enhances energy expenditure by activating thermogenic genes like UCP1 (96). Beyond its thermogenic effects, RA influences the cellular composition of AT by driving the commitment of preadipocytes to the beige lineage and supporting vascular development within the tissue. Improved vascularization not only optimizes the recruitment of progenitor cells but also provides a supportive microenvironment for beige adipocyte function, amplifying the metabolic benefits of vitamin A (Fig. 2D) (97,98).

In parallel, vitamin D plays a distinct but indirect role in modulating AT and ILC2-driven immune responses. Immune cells express the vitamin D receptor (VDR), but its expression varies widely among cell types. While monocytes, neutrophils, and macrophages exhibit high VDR expression, ILC2s display very low or negligible VDR levels (99). This suggests that vitamin D does not act directly on ILC2s but rather influences their function through its effects on other immune cells within the adipose microenvironment. For instance, vitamin D promotes type 2 immune responses by supporting M2 macrophage polarization and eosinophil recruitment, processes that align with ILC2-mediated inflammation resolution. Additionally, vitamin D mitigates pro-inflammatory signals in AT and supports the beiging of white adipocytes, which enhances metabolic health and improves insulin sensitivity (100). Together, vitamins A and D exert complementary effects on AT function, promoting thermogenic activity, reducing inflammation, and fostering a microenvironment conducive to metabolic homeostasis.

CONCLUSIONS

This review underscores the critical role of intracellular metabolism in shaping the functions of ILCs and highlights the tissue-specific metabolic cues that regulate their distinct attributes. ILCs, as tissue-resident cells, are uniquely influenced by the metabolic environment of their local niche. Recent advances reveal that ILC subsets exhibit distinct metabolic preferences that align with their activation states and functional requirements. For instance, NK cells, ILC1s, and ILC3s predominantly rely on glycolysis during activation and proliferation, while ILC2s demonstrate a strong dependence on FAO and synthesis for their effector functions. These divergent metabolic pathways underscore the pivotal role of immune-metabolism in regulating ILC activation and subset-specific functions.

Moreover, a wide array of metabolites—including SCFAs, vitamins, and AAs—has been shown to modulate ILC activity. These metabolites, often unique to specific tissues, shape the behavior of resident ILCs, influencing immune responses and contributing to disease pathogenesis. Interactions between ILCs and the local metabolic milieu highlight a dynamic interplay that has profound implications for tissue homeostasis and inflammation. The growing body of evidence linking metabolism to ILC function suggests that targeting immunometabolic pathways could provide novel strategies for managing tissue-specific diseases. By limiting and/or providing various metabolites, dietary fiber to vitamin supplements, ILCs’ function could be regulated and which serve as a pivotal role in tissue immunity. Therefore, supplying metabolites with conventional therapy could help boosting treatment potency.

The interaction between ILCs and tissue-specific metabolites is an emerging field with significant potential to deepen our understanding of immune regulation. While research on these interactions is still limited, metabolites in the tissue microenvironment play crucial roles in modulating ILC function and influencing local immune responses. Future studies should focus on identifying possible metabolites that could regulate ILCs across different tissues, exploring the molecular mechanisms underlying these interactions, and investigating their therapeutic potential in diseases like IBD, asthma, atopic dermatitis, and obesity. A deeper understanding of how tissue-derived metabolites influence ILC activity will also provide valuable insights into the pathogenesis of inflammatory, metabolic, and immune-mediated disorders, potentially leading to therapeutic strategies that modulate ILC metabolism to restore tissue health and immune balance.

Abbreviations

1,25D

1,25-dihydroxyvitamin D3

2-DG

2-deoxyglucose

AA

amino acid

ACC1

acetyl-CoA carboxylase 1

AD

atopic dermatitis

AHR

airway hyperresponsiveness

AhR

aryl hydrocarbon receptor

Arg1

arginase-1

AT

adipose tissue

CRAC

Ca²⁺ release-activated Ca²⁺

CRSwNP

chronic rhinosinusitis with nasal polyps

DGAT1

diacylglycerol O-acyltransferase 1

DRD1

dopamine receptor D1

DSS

Dextran sulfate sodium

FA

fatty acid

FAO

fatty acid oxidation

Ffar

free fatty acid receptor

GPR

G-protein-coupled receptor

HIF

hypoxia-inducible factor

Hk2

hexokinase-2

IBD

inflammatory bowel disease

ILC

innate lymphoid cell

LKB1

liver kinase B1

LT

leukotriene

mTORC

mTOR complex

NFAT2

nuclear factor of activated T-cells 2

NPM1

nucleophosmin 1

OCR

oxygen consumption rate

OXPHOS

oxidative phosphorylation

PGD₂

prostaglandin D₂

PPAR

peroxisome proliferator-activated receptor

RA

retinoic acid

RXRγ

retinoid X receptor gamma

SCFA

short-chain fatty acid

SREBP

sterol regulatory element-binding protein

TFAM

mitochondrial transcription factor A

TfR1

transferrin receptor 1

Trp

tryptophan

UCP

uncoupling protein

UVB

ultraviolet B

VDR

vitamin D receptor

VHL

von Hippel-Lindau