This study shows that CAF-derived exosomal miR-196a has the ability to promote the cisplatin resistance of HNSCC by targeting cyclin dependent kinase inhibitor 1B (CDKN1B) and inhibitor of growth family member 5 (ING5), leading to cell proliferation and inhibiting cell apoptosis. Here, CDKN1B is linked to head and neck squamous cell carcinoma.