Core regulatory mechanisms of macrophage dynamic polarization and multicellular interaction networks in driving...

Venous thromboembolism (VTE) is one of the leading causes of cardiovascular-related mortality worldwide. Its pathogenesis is complex, and current treatment strategies centered on anticoagulation face challenges such as high bleeding risks and limited efficacy in dissolving established thrombi. In recent years, research in the field of VTE has increasingly focused on the "inflammation-thrombosis" interaction, with macrophages emerging as a central regulator in this process, highlighting the growing importance of related studies. Through dynamic phenotypic polarization into pro-inflammatory M1 and anti-inflammatory M2 states, macrophages contribute to both thrombus formation and resolution. In the early stages of thrombogenesis, M1 macrophages establish a pro-inflammatory milieu by secreting chemokines, promoting leukocyte infiltration, enhancing platelet activation, and facilitating fibrin deposition, ultimately contributing to thrombus stabilization. Conversely, M2 macrophages play a central role in thrombus resolution by secreting matrix metalloproteinases (MMPs) and cytokines that promote fibrinolysis and endothelial repair. These polarization states are tightly regulated by hypoxia, metabolic reprogramming, and intercellular signals from endothelial cells, platelets, and neutrophils, forming an intricate multicellular regulatory network. Additionally, macrophages engage in exosome-mediated communication and immunomodulation, further amplifying thrombus-associated inflammation and vascular remodeling. Targeting macrophage polarization-particularly enhancing the M2 phenotype or disrupting chemotactic signaling pathways-has shown promise in reducing thrombus burden in preclinical models. Understanding the spatial-temporal heterogeneity of macrophage subsets and their interactions with other cell types may uncover novel therapeutic targets. This review summarizes current advances in macrophage biology in VTE, emphasizing their dual functional roles and regulatory networks. A better understanding of macrophage-driven immune-thrombotic crosstalk holds potential to refine current treatments beyond anticoagulation and to develop precision immunotherapies for VTE.