Role of Smad4 loss in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a major malignancy with poor improvement in outcomes over the past two decades. This work identifies Smad4 loss as a causal driver of HNSCC development. Conditional deletion of Smad4 in mouse head and neck epithelia led to spontaneous HNSCC accompanied by genomic instability, reduced expression of Fanconi anemia/Brca pathway genes, and heightened inflammation marked by elevated TGFβ1‑dependent cytokines. Smad4-deficient keratinocyte stem cells also displayed abnormal proliferation and retained multipotency. Together, these findings show that Smad4 loss promotes HNSCC through combined effects on genomic integrity, inflammatory signaling, and stem cell dysregulation.