Extracellular vesicles derived from cancer-associated fibroblasts facilitate NSCLC progression and metastasis via miR-664b-5p-mediated activation of the CXCL12/CXCR4 chemokine pathway.

Exosomal miRNAs mediate intracellular communication between the tumor microenvironment and cancer cells in non-small cell lung cancer (NSCLC). However, effects of exosomal miRNAs on NSCLC and its mechanisms have not been completely clarified. Here, exosome miRNA profiling and patient serum analysis revealed that the expression level of exosomal miR-664b-5p is significantly elevated in NSCLC, with particularly high levels in cancer-associated fibroblasts (CAFs) and their secreted exosomes. Functionally, miR-664b-5p promotes cell proliferation, migration, and invasion and inhibits apoptosis, thereby promoting malignant progression and metastasis in NSCLC. Moreover, experiments in a CAF-organoid coculture system and a CAF-NSCLC cell coinjection animal model demonstrated that exosomal miR-664b-5p is derived primarily from CAFs and is transferred to NSCLC cells via exosomes, contributing to the malignant phenotype of NSCLC cells, whereas miR-664b-5p knockdown in CAFs attenuated their tumor-promoting ability. Further exploration revealed that G protein γ subunit 11 (GNG11) is a direct functional target gene of miR-664b-5p. GNG11 expression is negatively correlated with miR-664b-5p expression, and ectopic expression of GNG11 partially abrogates the malignant phenotypes induced by miR-664b-5p overexpression in NSCLC. Mechanistically, CAF-derived exosomal miR-664b-5p facilitates NSCLC progression and metastasis by downregulating GNG11, which correlated with activation of the CXCL12/CXCR4 chemokine pathway. Serum exosomal miR-664b-5p levels were positively correlated with tumor burden. Taken together, the results of our study reveal that exosomal miR-664b-5p derived from CAFs can be transferred to NSCLC cells to promote NSCLC progression and metastasis via the CXCL12/CXCR4 axis, supporting the potential of exosomal miR-664b-5p as a biomarker and therapeutic target for NSCLC.