Immunometabolic control of ILC3s: implications for epithelial barrier homeostasis and inflammation

Group 3 innate lymphoid cells (ILC3s) residing in barrier tissues are pivotal for maintaining epithelial integrity, regulating microbial homeostasis, and coordinating immune responses to inflammatory challenges. Emerging evidence indicates that ILC3s function extends beyond cytokine secretion and is tightly orchestrated by intrinsic metabolic programming. Core metabolic pathways including glucose, lipid, and amino acid metabolism, along with key regulatory hubs such as AMP-activated protein kinase (AMPK), sirtuins, and mechanistic target of rapamycin complex 1 and 2 (mTORC1/2), integrate nutrient and energy cues to control ILC3s abundance, phenotype and effector activity. Notably, ILC3s exhibit remarkable metabolic plasticity across distinct tissue microenvironments: glycolysis and oxidative phosphorylation support rapid effector responses, whereas lipid and amino acid metabolism sustain homeostatic functions and barrier protection through signaling regulation. Therapeutic strategies targeting ILC3s metabolism are emerging, encompassing modulation of AMPK/mTOR signaling pathway, supplementation with microbial-derived metabolites or dietary components, regulation of metabolic receptors and enzymes, and provision of metabolic intermediates. Nevertheless, a comprehensive framework linking ILC3s metabolic profiles to their functional outputs remains lacking, particularly under inflammatory conditions and in tissue-specific contexts. Future studies integrating single-cell metabolomics, spatial multi-omics, and metabolic flux tracing will be essential for systematically defining the metabolic-functional network of ILC3s. Such efforts will deepen mechanistic understanding and provide a foundation for developing metabolism-based strategies against epithelial barrier dysfunction-associated diseases.