The platelet-neutrophil metastatic circuit in breast cancer: from pulmonary pre-metastatic niche formation to hydrogel-guided therapeutic intervention

Breast cancer lung metastasis remains a major determinant of therapeutic resistance and cancer-associated mortality, arising from the coordinated interplay between tumor cell plasticity and the systemic metastatic microenvironment. Increasing evidence identifies the platelet–neutrophil axis as an important, context-dependent immunothrombotic contributor of metastatic dissemination, yet its integrated role in pulmonary colonization remains insufficiently addressed. Activated platelets often support the survival of circulating tumor cells (CTCs) through immune and mechanical shielding and facilitate endothelial adhesion and pulmonary arrest. However, their effects vary by target, timing, metastatic route, and organ. Neutrophils are similarly context-dependent: tumor-entrained states may restrict seeding, whereas cytokine-reprogrammed or neutrophil extracellular trap (NET)-forming states promote matrix remodeling, endothelial activation, immunosuppression, and colonization. Human evidence includes platelet-coated CTCs, CTC–neutrophil clusters, tissue NETs, and prognostically relevant circulating NET markers in metastatic breast cancer. Importantly, reciprocal signaling between platelets and neutrophils establishes a self-reinforcing thromboinflammatory circuit characterized by selectin-mediated adhesion, chemokine amplification, NETosis, and microvascular immunothrombosis, thereby generating a permissive pre-metastatic and metastatic lung niche. In this review, we comprehensively synthesize current mechanistic and translational evidence implicating platelet–neutrophil cooperation as a potentially important regulator of breast cancer pulmonary metastasis, with particular emphasis on the molecular pathways that govern immunothrombosis, endothelial dysfunction, inflammatory signaling, and NET-mediated metastatic trapping. We further evaluate hydrogel-enabled interventions using an evidence-tiered framework that distinguishes breast cancer-specific in vivo efficacy from cross-tumor proof of concept and mechanistically motivated design. Direct evidence for circuit-oriented hydrogel therapy in breast cancer is currently limited to localized NET-degrading combination treatment after incomplete 4T1 tumor resection. In contrast, genuinely NET-triggered materials and platelet-mimetic hydrogels have not yet demonstrated efficacy against breast cancer lung metastasis. Accordingly, these emerging architectures are presented as testable strategies to improve spatial control and limit systemic toxicity, rather than as established precision antimetastatic platforms. By integrating metastatic immunobiology with advanced biomaterials engineering, this framework positions the platelet–neutrophil axis not only as a mechanistically relevant circuit of breast cancer lung metastasis but also as a potentially actionable therapeutic vulnerability for precision antimetastatic intervention.