Integrated Multi-Omics Analysis for Molecular Subtyping in NSCLC: A Cohort Study

Lung cancer remains the leading cause of cancer–related morbidity and mortality worldwide, with non–small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Current histopathological classification and driver gene testing provide limited prognostic and therapeutic guidance due to intra–tumoral heterogeneity and incomplete characterization of the tumor microenvironment (TME). Here, we constructed single– and multi–omics molecular classification systems for NSCLC by integrating transcriptomic, genomic, epigenomic, proteomic, and TME data from TCGA LUAD and LUSC cohorts. Single–omics analyses revealed distinct molecular patterns, including DNA methylation subtypes associated with sex and histology. Multi–omics integration identified five consensus subtypes closely corresponding to histology, with three immune–activated (CS2–CS4) and two immunosuppressive (CS1, CS5) subtypes. While overall survival did not differ significantly, progression–free survival analysis highlighted CS4 as a high–risk subtype with KRAS–driven genomic alterations. These findings provide a framework for NSCLC molecular stratification and highlight molecular and immune features that could guide future research on targeted therapies and immunotherapy.