Neutrophil-mediated modulation of tumor angiogenesis: From proangiogenic mediators to extracellular vesicles

Angiogenesis is a tightly controlled physiological process that enables the formation of new blood vessels. Under normal conditions, it is regulated by a balance between pro- and anti-angiogenic signals. In cancer, this equilibrium is disrupted, and angiogenesis becomes a pathological mechanism that supports tumor growth, progression, and metastasis. The process is orchestrated by a variety of cells, including endothelial cells (EC), fibroblasts, macrophages, platelets, neutrophils, and cancer cells, which release chemical mediators. Among them, growth factors such as VEGF, FGF, PDGF, angiopoietins, and TGF-β play a central role by activating signaling pathways that stimulate endothelial proliferation, migration, survival, and extracellular matrix (ECM) remodeling. Their activity drives the "angiogenic switch," a hallmark of early tumor development. Neutrophils, the most abundant immune cells in circulation, exert a dual influence on this process. Pro-tumor neutrophils enhance angiogenesis through the secretion of VEGF-A, TGF-β, MMP-9, IL-8, and the release of neutrophil extracellular traps, facilitating vascular permeability and tumor progression. Conversely, anti-tumor neutrophils release TNF-α, IL-12, and chemokines such as CXCL9/10, which inhibit angiogenesis and restrain tumor expansion. Recently, small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication. Neutrophil-derived sEVs transport proangiogenic miRNAs, proteins, and signaling molecules that influence endothelial activation, epithelial-to-mesenchymal transition, therapy resistance, and metastatic potential. Given their unique molecular cargo, they represent potential modulators of tumor angiogenesis, although studies in this area remain limited. This review summarizes the principal mechanisms of angiogenesis, the multifaceted role of neutrophils in shaping tumor vasculature, and the emerging contribution of neutrophil-derived sEVs.