Lung cancer cell-derived exosomal EHF drives M2 macrophage polarization via transcriptional activation of RNF41 to promote tumor progression.

M2 macrophage polarization in the tumor microenvironment drives lung cancer progression. ETS homologous factor (EHF) is overexpressed in lung cancer and linked to malignancy. However, the mechanism by which EHF regulates macrophage M2 polarization in the lung cancer microenvironment remains unclear. EHF expression in lung cancer tissues was assessed via bioinformatics databases, qRT-PCR, and Western blot. Cell proliferation, glycolysis indices, apoptosis, and migration were evaluated via EdU, commercial kits, flow cytometry, and Transwell, respectively. Lung cancer cell exosomes were isolated, with their characteristics identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Next, the binding between ring finger protein 41 (RNF41) and EHF was predicted via JASPER and verified by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. EHF was highly expressed in lung cancer. Downregulation of EHF suppressed the malignant phenotypes of lung cancer cells and reduced M2 polarization of macrophages. Exosomes from lung cancer cells could enrich EHF and deliver it to macrophages, promoting their M2 polarization, while knockdown of EHF in exosomes reversed this effect. Mechanistically, EHF bound to the RNF41 promoter and promoted its transcription, and overexpression of RNF41 could reverse the suppressive effects of EHF silencing on macrophage M2 polarization and lung cancer progression. In vivo experiments showed that inhibition of the EHF/RNF41 axis significantly suppressed tumor growth. Exosomal EHF derived from lung cancer cells promoted M2 polarization of macrophages through transcriptional regulation of RNF41, thereby driving lung cancer progression.