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Tumoral extracellular vesicles and particles reprogram interstitial macrophages in the lung to promote vascular permeability and metastasis
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DOI：10.1038/s43018-026-01209-z.png)
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Abstract
En 中文
The mechanisms by which tumor-derived extracellular vesicles and particles (EVPs) promote vascular permeability during premetastatic niche formation remain unclear. Here, we show that tumor EVPs rapidly induce vascular leakiness within 1 h of administration in female mice, creating a permissive environment that enhances metastatic seeding. Rather than acting directly on endothelial cells, EVPs activate NF-κB and JAK–STAT signaling in interstitial macrophages, leading to IL-6 secretion and increased vascular permeability. Interstitial macrophage depletion markedly reduces EVP-induced vascular leakiness and metastasis. We identify extracellular vesicle-associated integrin α5 (ITGα5) as a major functional determinant of this process, promoting macrophage activation and IL-6 secretion without affecting EVP uptake. EVPs derived from colorectal cancer tumors with high ITGα5 similarly induce macrophage IL-6 secretion and vascular permeability. Together, these findings define an EVP–macrophage–IL-6 axis that drives vascular permeability during premetastatic niche formation and identify EVP-associated ITGα5 as a key mediator of metastatic progression and a potential therapeutic target. Dror et al. show that tumor-derived extracellular vesicles and particles reprogram interstitial macrophages during the formation of the lung premetastatic niche, thereby increasing vascular permeability and promoting metastatic potential.
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