Abstract
BACKGROUND: Lung adenocarcinoma (LUAD) is a major contributor to cancer mortality and exhibits high intratumoral heterogeneity. The functional role of SPATS2 in LUAD remains poorly defined. METHODS: We integrated transcriptomic data from TCGA, GTEx, and GEO databases to evaluate SPATS2 expression patterns and their associations with clinical features and prognosis in LUAD. Genomic analyses were performed to assess copy number variations, mutation correlations, and tumor mutation burden (TMB). Functional enrichment analyses (GSEA, GSVA) and immune infiltration profiling (CIBERSORT, ESTIMATE, TIP) were conducted to explore the biological and immunological roles of SPATS2. Single-cell RNA sequencing data from the TISCH database (GSE131907) were used to determine SPATS2 expression in tumor microenvironment (TME) cell subsets. In vitro experiments using siRNA-SPATS2 in A549 cells were performed to assess mitochondrial function. RESULTS: SPATS2 expression was significantly elevated in LUAD tissues and correlated with copy number amplification and increased TMB. High SPATS2 levels were associated with advanced stage, lymph node metastasis, and worse overall survival. Functional analyses revealed enrichment in cell cycle, DNA repair, and metabolic pathways. Immune profiling indicated that SPATS2 modulates immune infiltration, with higher expression linked to increased infiltration of macrophages and Tregs, and reduced stromal and immune scores. Single-cell data showed SPATS2 expression was highest in endothelial and plasma cells. Knockdown of SPATS2 impaired mitochondrial membrane potential and reduced ROS levels in A549 cells. CONCLUSION: SPATS2 is a potential prognostic biomarker and therapeutic target in LUAD. Its role in tumor progression, immune remodeling, and mitochondrial function warrants further investigation in personalized therapy development.