BACKGROUND: Lung cancer is the leading cause of cancer deaths globally, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being major subtypes. Immunotherapy has emerged as a promising approach for the treatment of lung cancer, but understanding the underlying mechanisms of immune dysregulation is crucial for the development of effective therapies. This study aimed to investigate the distinctive cellular features of LUAD and LUSC and identify potential biomarkers associated with the pathogenesis and clinical outcomes of each subtype. METHODS: We used digital cytometry techniques to analyze the RNA-Seq data of 1128 lung cancer patients from The Cancer Genome Atlas (TCGA) database. The abundance of cell subtypes and ecotypes in LUAD and LUSC patients was quantified. Univariate survival analysis was used to investigate their associations with patient overall survival (OS). Differential gene expression analysis and gene co-expression network construction were carried out to explore the gene expression patterns of LUSC patients with distinct survival outcomes. Scratch wound-healing assay, colony formation assay, and transwell assay were used to validate the candidate drugs for LUSC treatment. RESULTS: We found differential expression of cell subtypes between LUAD and LUSC, with certain cell subtypes being prognostic for survival in both subtypes. We also identified differential gene expression and gene co-expression modules associated with macrophages.3/PCs.2 ratio in LUSC patients with distinct survival outcomes. Furthermore, ecotype ratios were found to be prognostic in both subtypes and machine learning models showed that certain cell subtypes, such as epithelial.cells.1, epithelial.cells.5, and endothelial.cells.2 are important for predicting LUSC. Ginkgolide B and triamterene can inhibit the proliferation, invasion, and migration of LUSC cell lines. CONCLUSION: We provide insight into the distinctive cellular features of LUAD and LUSC, and identify potential biomarkers associated with the pathogenesis and clinical outcomes of each subtype. Ginkgolide B and triamterene could be promising drugs for LUSC treatment.