Synergistic effects of neutrophil extracellular traps and NF-κB on promoting tumor progression and immune evasion in lung adenocarcinoma.

Aberrant activation of NF-κB and the formation of neutrophil extracellular traps (NETs) play pivotal roles in the progression of lung adenocarcinoma (LUAD). This study aimed to explore the function roles of NF-κB and NETs in tumor development and immune evasion. Among clinical patients received first-line chemoimmunotherapy, patients with stable disease (SD) or progressive disease (PD) exhibited higher levels of NETs and NLR compared to the patients with complete response (CR) or partial response (PR). Based on data from The Cancer Genome Atlas (TCGA) and RNA-seq datasets GSE135222 and GSE126044, a strong association between elevated neutrophil-lymphocyte ratio (NLR) and unfavorable clinical outcomes in LUAD patients was identified. Notably, the NET score was positively correlated with NLR. In vitro experiments showed NETs enhanced NF-κB activation in LUAD cells. NETs and NF-κB synergistically promoted proliferation and invasion of LUAD cells, as verified by CCK-8 and transwell assays. Additionally, NETs and NF-κB cooperatively upregulated CD47 protein expression, thereby enabling evasion of macrophage-mediated phagocytosis. In vivo experiments using subcutaneous and lung metastasis models revealed that NETs and NF-κB not only promoted tumor growth but also altered the tumor immune microenvironment. Inhibition of NET formation by DNase effectively suppressed tumor progression and immune evasion. Altogether, our findings indicate that in LUAD, NETs or NF-κB pathways collaborate to enhance their roles in the tumor process and may represent a promising therapeutic target.