Abstract
Macrophages exhibit remarkable functional plasticity by dynamically polarizing into proinflammatory or antiinflammatory subsets in response to microenvironmental cues. This duality underpins their pivotal roles in immune defense, tissue homeostasis, and disease progression; however, the molecular mechanisms governing their polarization and crosstalk across various pathologies remain incompletely defined. This review systematically delineates macrophage biology, emphasizing the interplay between subset-specific signaling networks and their context-dependent activation in both health and disease. The heterogeneity of macrophages is characterized by detailing the distinctions between tissue-resident and monocyte-derived origins, as well as their polarization states. Core pathways regulating phagocytosis, tissue repair, immune modulation, and neuroprotection are dissected, along with their dysregulation in autoimmune disorders, neurodegeneration, cancers, and cardiovascular diseases. Notably, microenvironmental factors such as damage-associated molecular patterns, pathogen-associated molecular patterns, and metabolic intermediates dynamically reshape macrophage phenotypes through NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation or signal transducer and activator of transcription (STAT)-mediated transcriptional control. Preclinical and clinical evidence underscores potential therapeutic targets and emerging strategies. The significance of this review lies in its integrative analysis of signaling crosstalk, paradoxical pathway roles, and translational implications for precision therapies. These insights into macrophage functions and signaling pathways provide a robust foundation for future disease intervention and personalized medicine.