The exosomal miRNA/FOXN3 axis empowers fibroblasts with tumor-promoting functions via enhanced migration and altered secretome

Malignant tumor tissues with high proliferative activity are frequently characterized by a rich abundance of cancer-associated fibroblasts (CAFs). Nevertheless, the precise molecular mechanisms by which CAF-tumor cell crosstalk drives malignant proliferation remain incompletely elucidated. In this study, we demonstrate that exosomal microRNAs derived from lung adenocarcinoma cells reprogram adjacent normal fibroblasts into CAFs through downregulation of their common target, FOXN3. Suppression of this transcriptional repressor enhances the expression of genes associated with cell migration and extracellular matrix remodeling, thereby potentiating CAF infiltration into the tumor core. The consequent spatial proximity between CAFs and tumor cells enables the aberrantly altered secretome of CAFs to exert robust paracrine effects on malignancy. By focusing on receptors that interact with these dysregulated secreted proteins, we evaluated the drug sensitivity of patients bearing highly proliferative tumors to receptor-targeting agents, revealing potential therapeutic opportunities. Collectively, our work offers a detailed molecular dissection of tumor cell proliferation and proposes translationally relevant strategies for cancer therapy.