Platelet–neutrophil cooperation in premetastatic niche formation: from NETosis and stromal conditioning to nanotherapeutic interception

Metastasis remains the leading cause of cancer-related mortality, yet the metastatic cascade is initiated long before circulating tumor cells reach distant organs. Central to this early phase is the premetastatic niche (PMN), a dynamic and tumor-conditioned microenvironment in which vascular, stromal, metabolic, and immune compartments are progressively reprogrammed to support metastatic seeding. Among the mechanisms that orchestrate this process, platelet–neutrophil crosstalk has emerged as a critical thromboinflammatory axis linking hemostatic activation to innate immune remodeling and niche permissiveness. Tumor-derived signals activate platelets, which in turn engage neutrophils through key adhesive pathways, including P-selectin–PSGL-1 and GPIbα–Mac-1, thereby promoting platelet–neutrophil aggregation, endothelial dysfunction, microthrombus formation, and local inflammatory amplification. This interaction is further reinforced by neutrophil extracellular traps (NETs), which function as extracellular scaffolds that trap circulating tumor cells, remodel the extracellular matrix, expose pro-adhesive ligands, and protect malignant cells from immune surveillance. Together, platelet activation, neutrophil reprogramming, and NETosis establish a self-amplifying immunothrombotic niche that facilitates vascular arrest, tumor-cell survival, and metastatic colonization. Despite this mechanistic progress, important translational gaps remain, including limited human validation, the absence of robust biomarkers for PMN activity, and an incomplete understanding of species-specific differences in platelet–neutrophil biology. This review synthesizes current evidence on the molecular basis of platelet–neutrophil cooperation in PMN formation and discusses emerging anti-metastatic strategies, with particular emphasis on anti-adhesion approaches, anti-NET interventions, and stimuli-responsive nanotherapeutic platforms designed to deliver anti-platelet, anti-inflammatory, and anti-NET agents to nascent metastatic niches. Collectively, these data support the platelet–neutrophil–NET axis as a compelling therapeutic and biomarker-focused target for early metastasis interception.