Multi-omics profiling identifies ADAM9 as a key efferocytosis driver in lung adenocarcinoma

Objective Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, necessitating identification of novel biomarkers for precision therapy. Herein, we aimed to investigate the role of efferocytosis-related genes (ERGs) in LUAD progression, focusing on ADAM9 as a potential prognostic and therapeutic target. Methods TCGA-LUAD datasets including 517 tumor and 59 normal tissues were applied to perform consensus clustering, LASSO regression, and immune infiltration algorithms. A prognostic model was constructed and validated via survival analysis and nomogram. Single-cell sequencing was performed to analyze the distribution of ADAM9 in tumor microenvironment. Additionally, in vitro experiments were carried out to analyze the biological function of ADAM9 in LUAD progression. Results Eleven ERG signatures, including ADAM9, stratified patients into high- and low-risk groups with significant survival differences. A nomogram integrating ADAM9 and clinical features demonstrated robust predictive accuracy. High ADAM9 expression correlated with immunosuppressive microenvironments, characterized by increased M2 macrophages, neutrophils. Single−cell analysis identified predominant enrichment of ADAM9 in M2 macrophage subsets. Pseudotime trajectory analysis linked ADAM9 expression to M2 macrophage differentiation, while cell−cell interaction studies revealed ADAM9−high M2 macrophages as key signaling hubs in the tumor microenvironment. In vitro experiments demonstrated that ADAM9 silencing regulated efferocytosis and polarization in M2 macrophages, and subsequently suppressed tumor cell proliferation and migration via the IL-6/STAT3 signaling pathway. Conclusion Our study innovatively constructed a robust prognostic model based on ERG signatures. ERG signatures including ADAM9 not only precisely forecasted the survival outcomes and therapeutic responses of LUAD patients but also comprehensively uncovered the oncogenic role of ADAM9 in promoting tumor progression through multi-dimensional analysis.