EEF1G promotes cancer-associated fibroblast activation and drives lung cancer metastasis

Cancer-associated fibroblasts (CAFs) are crucial for tumor microenvironment remodeling and tumor metastasis. Eukaryotic elongation factor 1 gamma (EEF1G) is aberrantly expressed in many tumors, but its role in lung cancer metastasis, particularly via exosome-mediated CAF activation, remains unclear. This study investigated EEF1G’s mechanism in lung cancer metastasis through exosome-induced tumor–stroma interactions. We performed bioinformatics analyses, single-cell RNA sequencing, and in vitro experiments (cell culture, exosome isolation, Western blot, qRT-PCR, and immunofluorescence) to characterize the function of EEF1G. A tumor-fibroblast co-culture system and in vivo metastasis models validated the EEF1G–exosome–CAF axis and associated signaling. EEF1G was overexpressed in lung cancer tissues and exosomes, which correlated with poor prognosis and CAF infiltration. EEF1G promoted the proliferation, migration, and invasion of lung cancer cells. Mechanistically, tumor cells transferred exosomal EEF1G to fibroblasts, inducing CAF transformation via the activation of the NF-κB/ROS pathway, increased mitochondrial activity, and IL-6 secretion. Subsequently, CAF-derived IL-6-rich exosomes activated STAT3 in tumor cells, enhancing invasiveness. In vivo experiments confirmed that this exosome-mediated bidirectional communication robustly facilitates lung cancer metastasis. This study elucidates a novel EEF1G exosome-mediated pathway that activates CAFs, establishing a pro-oncogenic feedback network. We emphasize the critical NF-κB/ROS/IL-6/STAT3 signaling axis in tumor–stroma interactions, offering potential therapeutic targets for lung cancer.