Neutrophil Extracellular Trap-Derived DNA Activates the ITGB1/FAK Pathway to Promote Lung Adenocarcinoma Metastasis

Abstract Neutrophil extracellular traps (NETs) have recently emerged as key modulators of cancer progression and metastasis. However, a more comprehensive understanding of the underlying mechanisms could help identify effective strategies to prevent and treat NET-mediated metastasis. Here, we observed a marked accumulation of intratumoral NETs in metastatic primary lung adenocarcinoma (LUAD). Tumor cells with elevated CXCL2 expression not only recruited neutrophils via interactions with CXCR2 but also facilitated NET formation. In turn, NET-derived DNA (NET-DNA), through specific DNA motifs, directly bound to the extracellular domain of integrin β1 (ITGB1), thereby activating FAK signaling and promoting invasion and metastasis. NET-DNA was capable of enhancing CXCL2 expression through MAPK-ELK1, thereby establishing a positive feedback loop that maintained continuous neutrophil recruitment and NET formation. In both in vitro and in vivo models, targeting either NETs or ITGB1-FAK signaling significantly inhibited LUAD metastasis. These findings suggest that the CXCL2-NET-ITGB1-FAK signaling axis plays a pivotal role in driving NET-mediated metastasis, which provides a rationale for targeting this signaling pathway to inhibit LUAD metastasis.