Macrophages: Redefining extracellular matrix architecture through phenotypic switches as therapeutic targets

Macrophages, as central orchestrators of tissue homeostasis, exhibit remarkable developmental and functional plasticity across diverse physiological and pathological contexts. Mechanistically, microenvironmental cues govern phenotypic switching, while dysregulated crosstalk with stromal cells drives fibrosis and chronic inflammation. Emerging therapeutic strategies targeting macrophages demonstrate potential in restoring tissue homeostasis. However, challenges persist in achieving spatiotemporal precision and balancing pro-repair versus pro-fibrotic outcomes. This review synthesizes current understanding of macrophage biology, encompassing their developmental origins, phenotypic heterogeneity in tissue-specific niches, and multifaceted roles in extracellular matrix (ECM) remodeling, immune surveillance, and organ homeostasis. A comprehensive view of the macrophage regulatory landscape highlights that precise spatiotemporal regulation serves as the cornerstone for macrophages to restore tissue homeostasis. Multiple innovative strategies, including macrophage-based drug delivery systems, cellular and genetic engineering of macrophages, and synergistic macrophage treatment modalities, are expanding the technical frontiers for disease diagnosis and therapeutic intervention. Future directions emphasize integrating multi-omics profiling, synthetic biology, and AI-aided biomaterials to develop 'smart' therapeutics that dynamically steer macrophage functionality. Such synergy will unravel context-dependent signaling and subset-specific interactions, which further advances our understanding of macrophage biology and its translational potential in resolving refractory diseases, and bridges mechanistic insights into transformative clinical applications.