Metabolic regulation of tissue-resident immune cells: Molecular mechanisms and therapeutic implications

Many innate and adaptive immune cells are resident in non-lymphoid tissues and do not participate in peripheral circulation. These tissue-resident immune cells not only rapidly recognize and respond to local infections or injuries but also contribute to the maintenance of tissue homeostasis and immune balance. Immune cell function is closely associated with their metabolic state. Recent studies reveal that tissue-resident immune cells undergo unique metabolic reprogramming to adapt to their specific tissue microenvironment. This metabolic adaptation is crucial for their long-term survival, differentiation, and function. In this review, we systematically elaborate on the metabolic characteristics and tissue-specific regulatory mechanisms of CD8⁺ tissue-resident memory T cells (T_RM) and tissue-resident macrophages (TRMφs). Based on an in-depth analysis of the critical role of immunometabolic pathways in infection, cancer, and autoimmune diseases, we further summarize therapeutic strategies targeting these metabolic pathways and discuss their efficacy, potential side effects, and the challenges facing clinical translation.