Background:Lung adenocarcinoma (LUAD) is the most common variant of non–small cell lung cancer (NSCLC) across the world. Recently, the rapid development of immunotherapy has brought a new dawn for LUAD patients. Closely related to the tumor immune microenvironment and immune cell functions, more and more new immune checkpoints have been discovered, and various cancer treatment studies targeting these novel immune checkpoints are currently in full swing. However, studies on the phenotype and clinical significance of novel immune checkpoints in LUAD are still limited, and only a minority of patients with LUAD can benefit from immunotherapy.Methods:The LUAD datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the immune checkpoints score of each sample were calculated based on the expression of the 82 immune checkpoints-related genes (ICGs). The weighted gene co-expression network analysis (WGCNA) was used to obtain the gene modules closely related to the score and two different LUAD clusters were identified based on these module genes by the Non-negative Matrix Factorization (NMF) Algorithm. The differentially expressed genes between the two clusters were further used to construct a predictive signature for prognosis, immune features, and the response to immunotherapy for LUAD patients through a series of regression analyses.Results:A new immune checkpoints-related signature was finally established according to the expression of 7 genes (FCER2, CD200R1, RHOV, TNNT2, WT1, AHSG, and KRTAP5-8). This signature can stratify patients into high-risk and low-risk groups with different survival outcomes and sensitivity to immunotherapy, and the signature has been well validated in different clinical subgroups and validation cohorts.Conclusion:We constructed a novel immune checkpoints-related LUAD risk assessment system, which has a good predictive ability and significance for guiding immunotherapy. We believe that these findings will not only aid in the clinical management of LUAD patients but also provide some insights into screening appropriate patients for immunotherapy.