Background: Lung Squamous Cell Carcinoma (LUSC) is a major subtype of lung malignancies and is asso-ciated with the cause of cancer-mediated mortality worldwide. However, identification of transcriptomic signatures associated with survival-prognosis and immunity of tumor remains lackingMethod: The GSE2088, GSE6044, GSE19188, GSE21933, GSE33479, GSE33532, and GSE74706 were inte-grated for identifying differentially expressed genes (DEGs) with combined effect sizes. Also, the TCGA LUSC cohort was used for further analysis. A series of bioinformatics methods were utilized for conduct-ing the whole study.Results: The 831 genes (such as DSG3, PKP1, DSC3, TPX2, and UBE2C) were found upregulated and the 731 genes (such as ABCA8, SELENBP1, FAM107A, and CACNA2D2) were downregulated in the LUSC. The func-tional enrichment analysis identifies the upregulated KEGG pathways, including cell cycle, DNA replica-tion, base excision repair, proteasome, mismatch repair, and cellular senescence. Also, the key hub genes (such as EGFR, HRAS, JUN, CDH1, BRCA1, CASP3, RHOA, HDAC1, HIF1A, and CCNA2) were identified along with the eight gene modules that were significantly related to the protein-protein interaction (PPI). The clinical analyses identified that the overexpression group of CDH3, PLAU, PKP3, STIL, CALU, LOXL2, POSTN, DPP3, GALNT2, LOX, and ITPA are substantially associated with a poor survival prognosis and the downregulated group of IL18R1 showed a similar trend. Moreover, our investigation demonstrated that the survival-associated genes were correlated with the stromal and immune scores in LUSC, indicat-ing that the survival-associated genes regulate tumor immunity. The survival-associated genes were genetically altered in 27% of LUSC patients and showed excellent diagnostic efficiency. Finally, the con-sistent expression level of CDH3, PLAU, PKP3, STIL, CALU, LOXL2, POSTN, DPP3, GALNT2, and ITPA were found in the TCGA LUSC cohort Conclusions: The identification of key transcriptomic signatures can be elucidated by the crucial mecha-nism of LUSC carcinogenesis.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).