Methyltransferase-like 7B promotes M2-like macrophage polarization in lung adenocarcinoma via upregulating human epidermal growth factor receptor 3 expression and secretion.

M2-like tumor-associated macrophages form an immunosuppressive tumor microenvironment that drives tumor progression and limits therapeutic efficacy. Although methyltransferase-like 7B (METTL7B) acts as an oncogenic regulator of lung cancer, its non-cell-autonomous paracrine role in modulating macrophage polarization remains poorly characterized. In the present study, a public single-cell RNA sequencing dataset (GSE131907) and The Cancer Genome Atlas-Lung Adenocarcinoma (LUAD) cohort were integrated for bioinformatics screening and validation was performed using stable METTL7B-knockout A549 and METTL7B-overexpressing PC9 cell models. METTL7B was predominantly enriched in LUAD malignant epithelial cells and was positively correlated with human epidermal growth factor receptor 3 (ERBB3) expression. METTL7B upregulated both full-length and soluble ERBB3 isoforms and the METTL7B-induced elevation of ERBB3 ectodomain release was dependent on ADAM metallopeptidase domain 10/17-mediated proteolytic cleavage. Functionally, METTL7B promoted macrophage recruitment and induced functional M2 polarization via the soluble ERBB3 extracellular domain (ECD), with EGFR acting as the candidate receptor. Rescue and inhibition assays demonstrated that the ERBB3-EGFR axis mediated METTL7B-driven macrophage reprogramming. Clinically, the expression of both METTL7B and ERBB3 progressively increases with LUAD histological progression. The present findings delineate a novel METTL7B-ERBB3-ECD-EGFR paracrine axis in tumor-macrophage crosstalk, providing a potential therapeutic target for LUAD.