Niche-dependent immunometabolic regulation of tissue repair and regeneration

Abstract

Tissue repair restores structural integrity and functional homeostasis after injury through coordinated interactions among immune cells, structural compartments, and extracellular matrix remodeling, ultimately culminating in tissue-resident regenerative programs. Increasing evidence indicates that this process is governed not only by protein-based regulatory cues (e.g., inflammatory signals and growth factors) but also by dynamic immunometabolic adaptation within local repair niches. Given that repair is not executed through a uniform program across organs, distinct tissue architecture, physiological function, regenerative capacity, and injury-induced microenvironmental changes together define organ-specific repair demands and create specialized metabolic niches. Within these niches, immune cells adapt their metabolic states in response to hypoxia, nutrient availability, redox stress, dying-cell–derived (good-bye) signals, stromal cues, and mechanical constraints. These metabolic adaptations shape immune functions such as host defense, mediator production, efferocytosis, inflammation resolution, and support for tissue progenitors or differentiated parenchymal cells. In this review, we discuss how niche-specific immunometabolic regulation contributes to tissue repair across the intestine, skin, liver, lung, heart, and skeletal muscle. Rather than regarding immune metabolism as a general regulator of inflammation, we emphasize its context-dependent role in linking local repair demands to immune cell function and tissue-specific regenerative outcomes. Understanding these organ- and stage-specific metabolic checkpoints may provide a conceptual basis for developing targeted strategies to promote functional repair while limiting chronic inflammation, fibrosis, and maladaptive remodeling.