Cigarette Smoke Exposure Attenuates <scp>T2R</scp> ‐Mediated Apoptosis in Head and Neck Squamous Cell Carcinoma

BACKGROUND: Tobacco use is associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). Bitter taste receptor (T2R) activation induces apoptosis via calcium-dependent signaling, and higher T2R expression correlates with increased survival in HNSCC. However, the effects of cigarette smoke on T2R signaling remain unclear. METHODS: HNSCC cell lines were treated with cigarette smoke condensate (CSC). T2R expression was measured by qPCR, and function evaluated by calcium imaging, viability, and apoptosis assays following stimulation with denatonium benzoate and flufenamic acid. T2R expression was also assessed in patient-derived tumor tissue and The Cancer Genome Atlas (TCGA). RESULTS: CSC reduced T2R expression, impaired calcium signaling, and diminished T2R-mediated apoptosis, particularly in SCC47 cells. Lower expression was observed in CSC-exposed patient-derived tumor tissue and TCGA tumors from smokers versus nonsmokers. CONCLUSIONS: Cigarette smoke disrupts T2R signaling and reduces apoptosis in HNSCC, suggesting a mechanism by which ongoing tobacco use may alter tumor biology and treatment response.