Palmitic acid reprograms neutrophils to compromise vascular integrity and promote breast cancer lung metastasis.

Pre-metastatic niche formation in the lung creates a permissive microenvironment for breast cancer metastasis, characterized by metabolic reprogramming of resident cells, recruitment of suppressive neutrophils, and vascular remodeling. However, the role of lipids in regulating neutrophil-endothelial interactions, particularly in facilitating tumor cell extravasation, remains largely undefined. Here, we showed that triple-negative breast cancer established a palmitic acid-enriched lung microenvironment that drove tumor cell extravasation and colonization. Pulmonary endothelial cells were a major source of palmitic acid, which activated neutrophils to produce lipocalin-2 (LCN2) via the Toll-like receptor 4 (TLR4)-NF-κB pathway. Neutrophil-derived LCN2 disrupted endothelial tight junctions, compromised vascular integrity, and facilitated tumor cell extravasation. Targeting endothelial fatty acid synthesis using glucagon-like peptide-1 receptor agonists preserved vascular integrity and suppressed lung metastasis. These findings uncover a lipid-driven mechanism underlying metastatic organotropism and highlight metabolic intervention as a potential therapeutic strategy against breast cancer lung metastasis.