<p>Lung cancer, as one of the main causes of cancer-related deaths worldwide, has a high mortality rate and a poor prognosis. Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, which can regulate the behavior of cancer cells by secreting exosomes to transfer bioactive molecules. Homeobox C8 (HOXC8) is a homeobox gene that has been proven to be abnormally expressed in lung cancer, but the specific regulatory mechanism of it remains unclear. Firstly, CAFs, normal fibroblasts (NFs) and the exosomes secreted by them were separated and identified. The uptake of DIL-labeled exosomes by lung cancer cells was observed under a fluorescence microscope. Subsequently, the effects of CAFs-Exo and CAFs-Exo (si-HOXC8) on the viability, proliferation, apoptosis, migration, invasion, angiogenesis, and glycolysis of lung cancer cells were examined. Through bioinformatics analysis, Western blotting and qRT-PCR, the regulation of HOXC8 on Cyclin dependent kinase inhibitor 3 (CDKN3) in lung cancer cells was verified. A rescue experiment was carried out to investigate the effect of the HOXC8/CDKN3 axis on lung cancer cells. The CAFs-Exo was successfully extracted, which could be taken up by lung cancer cells. The upregulation of HOXC8 expression was found in CAFs-Exo. CAFs-derived exosomal HOXC8 deficiency hindered lung cancer cell viability, proliferation, migration, invasion, angiogenesis (endothelial cells), glycolysis, while facilitated apoptosis. HOXC8 could upregulate the expression of CDKN3. Besides, it was found that overexpression of CDKN3 can eliminate the inhibitory effect of knockdown of HOXC8 on lung cancer cells. The expression of HOXC8 in CAFs-Exo was upregulated, which could accelerate the growth, metastasis, glycolysis of lung cancer cells, and the angiogenic capacity of endothelial cells by facilitating the expression of CDKN3.</p> Graphical Abstract <p></p> <p>CAFs-derived exosomes stimulate the malignant progression of lung cancer cells through HOXC8/CDKN3 axis. The exosomes secreted by CAFs were rich in high levels of HOXC8, and these exosomes could promote the transcription process of CDKN3 gene, thereby increasing its expression. This change further promoted the proliferation, migration and invasion of lung cancer cells, and curbed the apoptosis of lung cancer cells. In addition, the process also stimulated angiogenesis and glycolytic metabolic pathways in lung cancer cells</p>