Neutrophil Spatiotemporal Regulatory Networks: Dual Roles in Tumor Growth Regulation and Metastasis

Neutrophils, accounting for 50-70% of circulating leukocytes, exhibit remarkable plasticity in tumor biology. Depending on tumor type and microenvironmental cues, they can exert either anti-tumor or pro-tumor effects. During tumor initiation, neutrophils exposed to chronic inflammation secrete cytokines and oncogenic microRNAs that promote genomic instability and malignant transformation. In tumor progression, neutrophils adopt context-dependent phenotypes and execute diverse functions, including polarization into anti-tumor (N1) or pro-tumor (N2) subsets; secretion of inflammatory and angiogenic mediators; formation of neutrophil extracellular traps (NETs); production of reactive oxygen and nitrogen species (e.g., H₂O₂ and nitric oxide); and modulation of immune cell infiltration and function within the tumor microenvironment. During metastasis, neutrophils facilitate cancer dissemination through three principal mechanisms: (1) promoting epithelial-mesenchymal transition (EMT) via inflammatory signaling, adhesion molecule interactions, and lipid metabolic support; (2) establishing pre-metastatic niches by remodeling distant organ stroma through NETs and matrix metalloproteinases; and (3) reactivating dormant tumor cells in response to chronic inflammation, viral infection, or stress hormones. Collectively, neutrophils function as central regulators across all stages of tumor evolution, influencing cancer growth, immune evasion, and metastatic progression. This review aims to provide a comprehensive synthesis of neutrophil-mediated mechanisms in the tumor microenvironment and highlight emerging strategies for neutrophil-targeted cancer therapy.