Research progress on the role and intervention of the macrophage-lymphatic vessel axis in chronic non-healing wounds

Chronic non-healing wounds, such as diabetic foot ulcers, venous ulcers, and burn wounds, represent a persistent clinical challenge due to delayed repair and high risk of complications. Studies have shown the role of macrophages in regulating lymphatic vessel formation and function through phenotypic transitions, forming what is referred to as the “macrophage–lymphatic axis”. This axis relies on IL-4/STAT6-VEGF-C/VEGFR-3-PI3K/Akt signaling, and coordinates lymphatic endothelial cell proliferation, migration, and lumen formation via paracrine signals, exosomes, and direct cell interactions. Despite differences in etiology, these chronic wounds share common features, including insufficient macrophage reparative polarization, impaired lymphangiogenesis, and compromised lymphatic drainage. Targeted Western medicine therapies, bioactive components of Traditional Chinese Medicine (TCM), and integrated TCM-Western medicine interventions can break the cycle of persistent inflammation and stalled repair by modulating multiple steps in these processes. This review summarizes current understanding of the macrophage-lymphatic axis in chronic wound repair, its dysregulation, and potential interventions.