The current study presents Sema4D expressed by HNSCC tumor cells, as a biomarker for dense fibrotic peri-tumoral stroma, and presents a novel role for Sema4D in modulating the tumor microenvironment through upregulation of ECM collagen production by fibroblasts, and TGF-β1 by tumor cells. Here, TGFB1 is linked to head and neck squamous cell carcinoma.