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Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a complex tumor microenvironment. Neddylation, as a type of post-translational modification, plays a vital role in the development of LUAD. To date, no study has explored the potential of neddylation-associated genes for LUAD classification, prognosis prediction, and treatment response evaluation.Methods: Seventy-six neddylation-associated prognostic genes were identified by Univariate Cox analysis. Patients with LUAD were classified into two patterns based on unsupervised consensus clustering analysis. In addition, a 10-gene prognostic signature was constructed using LASSO-Cox and a multivariate stepwise regression approach.Results: Substantial differences were observed between the two patterns of LUAD in terms of prognosis. Compared with neddylation cluster2, neddylation cluster1 exhibited low levels of immune infiltration that promote tumor progression. Additionally, the neddylation-related risk score correlated with clinical parameters and it can be a good predictor of patient outcomes, gene mutation levels, and chemotherapeutic responses.Conclusion: Neddylation patterns can distinguish tumor microenvironment and prognosis in patients with LUAD. Prognostic signatures based on neddylation-associated genes can predict patient outcomes and guide personalized treatment.