Background <p>Macrophages are central to innate immunity, orchestrating both the inflammatory and resolution phases of host defense. Emerging evidence indicates that immunometabolic crosstalk critically dictates macrophage polarization and functions. Disruptions in cellular metabolism can impair these regulatory mechanisms, leading to dysfunctional immune responses associated with various disease pathologies. A key aspect of this regulation involves metabolite-sensing receptors that detect changes in intracellular metabolic intermediates and in extracellular metabolites derived from the diet, host tissues, and the microbiome.</p> Methods <p>We have conducted a literature review of original research and review articles on metabolite-sensing receptors and their roles in immune cell function, drawn from central databases including PubMed and Google Scholar.</p> Results and Conclusion <p>A major class of extracellular metabolite-sensing receptors is G-protein-coupled receptors (GPCRs), which can directly or indirectly modulate macrophage activation, migration, cytokine production, and metabolic reprogramming. By fine-tuning macrophage-specific functions, metabolite-sensing receptors act as critical regulatory nodes in both inflammation and immune homeostasis, beyond their canonical role in sensing metabolic cues. This review provides a comprehensive overview of the metabolite-sensing receptor interactome, highlighting their central role in macrophage biology and underscoring their potential as therapeutic targets in inflammatory and metabolic diseases.</p>