Cancer-associated fibroblast-derived extracellular vesicles deliver ATP6V1C1 to promote lung adenocarcinoma metastasis via the ID1-IGFBP3 axis

Cancer-associated fibroblast (CAF)-derived extracellular vesicles (EVs) mediate lung adenocarcinoma (LUAD) progression, but the role of their protein cargo remains poorly defined. Through quantitative proteomic profiling of EVs from patient-derived CAFs, we identify the V-ATPase subunit ATP6V1C1 as a protein highly enriched in pro-migratory CAF-EVs that critically mediates LUAD metastasis. Mechanistically, EV-delivered ATP6V1C1 suppresses insulin-like growth factor binding protein 3 (IGFBP3) expression by downregulating the transcriptional regulator ID1. This suppression of IGFBP3 induces epithelial-mesenchymal transition in LUAD cells and amplifies the oncogenic IGF1/IGF1R/Akt/ERK signaling cascade initiated by CAF-secreted IGF1. This dual action establishes a feedforward loop that exacerbates metastatic progression. Our findings identify ATP6V1C1 as a dual regulator of LUAD metastasis and suggest a potential stroma-targeted therapeutic approach.