Volume 117, Issue 6, November 2025, 111147Author links open overlay panel, , , , , , , Highlights•

Based on the NETs score, the prognosis of LUAD patients in the high group was worse than in the low group.

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The NET-high group has a higher mutation burden, higher TIDE predicted MSI score and a poorer immunotherapy outcome.

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MEK inhibitors were more sensitive in the NET-high group and could inhibit the metastasis of LUAD.

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NETs-related signature was able to predict the prognosis and immunotherapy outcome of LUAD patients.

Abstract

Neutrophil extracellular traps (NETs) are a kind of DNA reticular structure that can capture and kill pathogenic microorganisms. NETs are closely related to the progression of tumors, but the role of NETs in the immunotherapy of lung adenocarcinoma (LUAD) remains unclear. We constructed a NETs-related prognosis signature based on ATG7, BST1, CEACAM3 and TNFRSF10C, and the prognosis of LUAD patients in the NET-high group was worse than NET-low group. At the same time, we constructed a nomogram to improve the validity of NETs-related signature and achieved good results in external datasets. The NET-high group was associated with a higher mutation burden, higher TIDE predicted MSI score and a poorer immunotherapy outcome. Finally, we found that MEK inhibitors (selumetinib and trametinib) were more sensitive in the NET-high group and can inhibit the invasion and migration of LUAD cells. The NETs-related signature was able to predict the prognosis and immunotherapy outcome of LUAD patients.

Keywords

neutrophil extracellular traps

NETs-related signature

immune therapy

lung adenocarcinoma

MEK inhibitor

Data availabilityThe external validation set can be downloaded from GEO database (Gene Expression Omnibus, https://www.ncbi.nlm.nih.gov/geo). All the codes, processed matrices and IHC scores are uploaded as supplementary materials.

© 2025 The Authors. Published by Elsevier Inc.