Single‐Cell Transcriptomics Identifies BST2 as an Oncogenic Driver and Immunotherapy Biomarker in Lung Adenocarcinoma

BACKGROUND: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality worldwide. The tumor microenvironment (TME) plays a pivotal role in LUAD progression, but the specific molecular mechanisms driving malignancy and immune evasion remain incompletely understood. Bone marrow stromal cell antigen 2 (BST2) has been implicated in other cancers, yet its functional role and therapeutic potential in LUAD require further elucidation. METHODS: We integrated single-cell RNA sequencing (scRNA-seq) data from primary LUAD tissues and normal lung tissues with bulk RNA-seq data from The Cancer Genome Atlas (TCGA)-LUAD and GEO cohorts. Malignant epithelial cells were identified using inferCNV analysis. Cellular trajectory and cell-cell communication analyses were systematically performed to delineate the malignant transformation process and its interactions with the TME. High-dimensional weighted gene coexpression network analysis further identified key functional modules within malignant subpopulations. The oncogenic role of BST2 was comprehensively validated through differential expression analysis, survival analysis, gene set enrichment analysis (GSEA), and in vitro cellular assays, including RT‑qPCR, MTT, colony formation, Transwell invasion, and wound healing experiments. In addition, we employed the tumor immune dysfunction and exclusion (TIDE) algorithm to evaluate its association with immunotherapy response and performed drug screening via the Clue.io platform to explore its therapeutic potential. RESULTS: scRNA-seq analysis revealed significant heterogeneity in the TME and identified two distinct subpopulations of malignant epithelial cells. Trajectory analysis uncovered a specific lineage (Lineage 4) driving the normal-to-malignant transition, while cell communication analysis highlighted interactions between malignant cells and tumor-associated macrophages (TAMs) mediated by MIF and APP signaling pathways. High-dimensional weighted gene coexpression network analysis (hdWGCNA) identified a coexpression gene module (Module 1) specifically enriched in malignant subpopulations. By intersecting with a set of immunoregulatory genes, BST2 was ultimately determined as a key candidate oncogene. BST2 was significantly upregulated in malignant epithelial cells and TAMs, and its high expression was closely associated with poor patient prognosis. GSEA demonstrated that high BST2 expression was linked to the activation of crucial oncogenic pathways, including oxidative phosphorylation, Kras signaling, and epithelial-mesenchymal transition (EMT). In vitro validation further confirmed that BST2 knockdown suppressed LUAD cell proliferation, migration, and invasion. Furthermore, elevated BST2 expression was associated with reduced efficacy of immune checkpoint blockade (ICB) therapy. CONCLUSION: Our study unveils BST2 as a critical oncogene in LUAD, promoting tumor progression and influencing the TME, particularly via TAM recruitment. BST2 expression predicts patient prognosis and immunotherapy response, positioning it as a promising biomarker and therapeutic target.