Herein, we provide in vitro and in vivo evidence that HNC0014 exhibits anti-HNSCC effects via inhibiting tumorigenic/stemness signature c-Met/STAT3/CD44/PD-L1, reducing cancer-associated fibroblast (CAF) transformation, and eliciting antitumor immune profiles. This evidence concerns the gene CD44 and head and neck squamous cell carcinoma.