The study identifies neutrophils as key drivers of metastatic establishment in the lung microenvironment of breast cancer models. Neutrophils, which are recruited to the pre-metastatic site, support metastatic initiation by expanding a sub-pool of cancer cells with high tumorigenic potential. This effect is mediated by neutrophil-derived leukotrienes (LTCs), specifically LTB4 and cysteinyl leukotrienes (CysLTs). Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) reduces metastasis. The findings suggest that targeting neutrophil Alox5 may limit metastatic progression, offering a potential therapeutic approach.The study identifies neutrophils as key drivers of metastatic establishment in the lung microenvironment of breast cancer models. Neutrophils, which are recruited to the pre-metastatic site, support metastatic initiation by expanding a sub-pool of cancer cells with high tumorigenic potential. This effect is mediated by neutrophil-derived leukotrienes (LTCs), specifically LTB4 and cysteinyl leukotrienes (CysLTs). Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) reduces metastasis. The findings suggest that targeting neutrophil Alox5 may limit metastatic progression, offering a potential therapeutic approach.