TBRG4 promotes malignant progression in lung adenocarcinoma: an integrated multi-omics and experimental study

Background Despite the identification of numerous biomarkers in lung adenocarcinoma (LUAD), few have been comprehensively investigated across multiple molecular and cellular dimensions. Consequently, their roles in tumor progression and tumor microenvironment remodeling remain incompletely understood. Methods Integrated multi-omics analyses were performed using transcriptomic and proteomic datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC), followed by clinical specimen validation and functional experiments, including short-hairpin RNA (shRNA)-mediated knockdown, in vitro assays, and xenograft models. Single-cell RNA sequencing, spatial transcriptomics, immune infiltration analyses, and an atezolizumab-treated cohort were further integrated to investigate the cellular context, tumor microenvironment, and prognostic relevance of TBRG4 in an atezolizumab-treated cohort. Results TBRG4 was consistently upregulated at both the transcriptomic and proteomic levels in LUAD, and elevated TBRG4 expression was associated with unfavorable overall survival across independent cohorts. Functional experiments showed that TBRG4 knockdown suppressed LUAD cell proliferation, migration, invasion, and xenograft growth and was accompanied by reduced PI3K-AKT phosphorylation and altered epithelial–mesenchymal transition-related marker expression, supporting a potential association with these molecular programs. Single-cell and spatial transcriptomic analyses localized TBRG4 predominantly to malignant epithelial cells and revealed associations with spatial heterogeneity, epithelial–stromal communication, immune microenvironment characteristics, and increased inferred copy-number variation burden. In the atezolizumab-treated OAK cohort, elevated TBRG4 expression was associated with poorer overall and progression-free survival, although its predictive value for immunotherapy response remains to be established. Conclusions Our findings suggest that TBRG4 represents a candidate biomarker associated with malignant progression and tumor microenvironment remodeling in LUAD and provide a comprehensive multi-omics framework for future mechanistic investigation and clinical validation.