Multi‐omics analysis highlights TM4SF4 + epithelial cells and the MMP14‐associated signaling program in lung adenocarcinoma pathogenesis and microenvironment remodeling

Lung adenocarcinoma (LUAD) progression is shaped by aberrant cell–cell and cell–matrix communication within a heterogeneous tumor microenvironment (TME). This study integrates single‐cell RNA sequencing (scRNA‐seq), genome‐wide association study, and spatial transcriptomics to identify epithelial subpopulations associated with this crosstalk. Analyzing GSE196303 scRNA‐seq data, we resolved 15 epithelial subpopulations. Using scPagwas, the TM4SF4 + subpopulation showed the highest trait‐relevance score for LUAD genetic susceptibility (adjusted p < 0.05). BayesPrism deconvolution of TCGA‐LUAD data revealed TM4SF4 + cell enrichment in tumors; high abundance was associated with poorer overall survival in the median‐cutoff analysis (hazard ratio = 1.43, 95% confidence interval = 1.07–1.92, p = 0.016) and with TME remodeling features (reduced immune/stromal scores and increased tumor purity). Weighted gene co‐expression network analysis and multi‐evidence intersection identified MMP14 as a candidate hub gene. Spatial transcriptomics supported the heterogeneous distribution of MMP14 , and functional enrichment linked MMP14 ‐associated transcriptional programs to ECM remodeling, migration, and Hedgehog/Notch pathways. Expression validation confirmed MMP14 upregulation in LUAD cells and tissues. Collectively, TM4SF4 + epithelial cells and the MMP14 ‐associated program may contribute to LUAD progression and TME remodeling, supporting them as candidate biomarkers and potential therapeutic targets for further validation.