Metabolic control of macrophages in coronavirus disease 2019

In the context of COVID-19, macrophages are primarily responsible for sensing and responding to the virus, significantly influencing disease outcomes. They are involved in early pathogen recognition, immune activation, and tissue repair. Heterogeneity and phenotypic plasticity of macrophages are dynamically shaped by microenvironmental cues, including metabolites, hypoxia, and pathogen-derived signals. Notably, emerging evidence underscores that cellular metabolism, particularly in macrophages, dictates immune responses to viral infection. This metabolic-immune crosstalk critically determines COVID-19 severity, ranging from viral clearance to hyperinflammation or fibrosis. In this review, we systematically dissect how cell-intrinsic metabolic nodes and extrinsic factors modulate macrophage effector functions, while illustrating the complications associated with macrophage metabolic dysregulation in SARS-CoV-2 infection. These mechanistic insights provide a rational foundation for therapeutic strategies targeting macrophage metabolism to rebalance immune responses and mitigate COVID-19 complications.