Chemokine CCL5 is transcriptionally suppressed by ΔNp63 and facilitates progression of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC), the eighth most common cancer globally, is characterized by poor prognosis and high metastatic potential. Although transcription factor ΔNp63 is known to promote HNSCC proliferation while suppressing epithelial-mesenchymal transition (EMT) and migration, its underlying molecular mechanisms remain unclear. Here, we demonstrate that ΔNp63 acts as a transcriptional repressor by directly binding to the promoter of CCL5 gene, which encodes a chemokine. We find that CCL5 is upregulated in HNSCC and drives cell proliferation and migration in vitro and in vivo. Further experiments reveal that CCL5 mediates ΔNp63's inhibitory effects on EMT, migration, and metastasis. Mechanistically, CCL5 triggers intracellular ERK signaling axis to promote EMT of HNSCC cells, leading to elevated in vitro migration and in vivo metastasis; on the other hand, CCL5 activates mTOR pathway, which may contribute to maintaining cell proliferation upon repression of ΔNp63. Additionally, CCL5 recruits and polarizes macrophages to the M2 phenotype, enhancing tumor infiltration. Antagonizing CCL5 receptor, CCR5, or blocking activation of the downstream mTOR or ERK pathway, effectively suppresses HNSCC progression. Our study uncovers the ΔNp63/CCL5 as a key regulatory axis of HNSCC metastasis and proliferation, proposing novel therapeutic targets for this malignancy.