Platelet-neutrophil cooperation in cancer: mechanisms of metastatic niche formation and implications for prognostic stratification and therapy.

Abstract

Metastasis remains the leading cause of cancer-related mortality and arises from ongoing interactions between malignant cells and their surrounding microenvironment. Among host factors, platelets and neutrophils have emerged as key regulators of metastatic potential. Growing evidence indicates that their coordinated activity-particularly through platelet-neutrophil aggregates（PNAs） and related mixed-cell complexes-forms an important but underrecognized pathway that promotes immune escape, vascular adaptation, and preparation of distant metastatic sites. This combination alters many critical steps in the spreading process. It includes survival within the circulation, evading the immune response, adhesion to the vessel wall and egress, and shifting target tissues. These are the result of collaborative mechanisms such as the use of soluble signaling factors, cell-cell adhesion, the NET-inflammatory response linked to coagulation, and the more persistent changes conferred by EVs and metabolism. Despite substantial progress in defining these mechanisms, important challenges limit clinical translation. Blood count-based platelet and neutrophil markers are not consistently used to assess metastatic risk across cancer types; the factors that control when and how neutrophils change functional states within tumors remain unclear; and therapeutic strategies that target platelet-neutrophil cooperation must carefully balance antimetastatic efficacy with risks such as bleeding and weakened host defense. In this review, we integrate current evidence on platelet-neutrophil-tumor interactions into a unified framework that connects biological mechanisms with clinically measurable indicators and therapeutic entry points. We examine emerging approaches to reduce metastasis supported by platelet-neutrophil interactions and NET-associated processes, consider how these strategies may complement existing cancer treatments, and emphasize the potential of combined biomarker models-such as integrating platelet measures with the neutrophil-to-lymphocyte ratio（NLR）-to improve prognostic assessment and guide future clinical validation.