Background <p>Cancer-associated fibroblasts (CAFs) represent a crucial component of tumor stroma and play critical roles in cancer progression. However, the role of CAFs derived exosomes in oral squamous cell carcinoma (OSCC) environment is unexplored. PIWI-interacting RNAs (piRNAs) serve as epigenetic effectors in cancer progression and constitute significant compositions of exosomes. Here, we explored the functional mechanism of exosomal piRNAs in OSCC development.</p> Methods <p>We screened exosomal piRNAs derived from CAFs and normal fibroblasts (NFs) and assess their effect on tumor proliferation and metastasis. A nude mouse model was established to assess the impact of exosomal piR-35462 on tumor progression.</p> Results <p>CAFs-derived exosomes showed an enhanced piR-35462 expression and promoted OSCC cell proliferation, migration and invasion. Additionally, elevated piR-35462 expression in OSCC tissues correlates with poor prognosis. Mechanistically, CAFs-derived exosomal piR-35462 increased the expression of fat mass and obesity-associated protein (FTO) in OSCC cells. By inhibiting N6-methyladenosine (m6A) RNA methylation, the overexpression of FTO further enhances the stability and expression levels of Twist1 mRNA, thereby contributing to epithelial-mesenchymal transition (EMT) and tumor progression. In vivo xenograft tumor model also confirmed the same results.</p> Conclusion <p>The achieved outcomes elucidate that CAFs can deliver piR-35462 containing exosomes to OSCC cells and promote OSCC progression via FTO/Twist mediated EMT pathways, and could represent a promising therapeutic target for OSCC.</p>