PANoptosis-based HNSCPAN-index predicts prognosis and reveals DSCAM as a therapeutic target in head and neck squamous cell carcinoma.

OBJECTIVE: To establish a prognostic PANoptosis-related gene signature in HNSCC and elucidate the role of Down syndrome cell adhesion molecule (DSCAM) in regulating tumor progression and immune evasion. METHODS: Differential expression and prognostic analyses were performed to define HNSCC subtypes based on PANoptosis-related genes. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to construct the HNSCPAN-index, which stratified patients into high- and low-risk groups. The predictive performance of this index was validated in independent cohorts. Associations with immune infiltration, mutation profiles, and drug sensitivity were also examined. Functional validation of DSCAM was conducted through in vitro and in vivo experiments. RESULTS: Six prognostically significant genes were identified and integrated into the HNSCPAN-index, which demonstrated independent prognostic value. Immunological landscape analysis showed that the low-risk group defined by the HNSCPAN-index was enriched in CD8+ T cells, follicular helper T cells, and memory-activated CD4+ T cells. Consistently, immune, stromal, and microenvironmental scores were significantly higher in the low-risk group. DSCAM knockdown suppressed proliferation and migration of HNSCC cell lines. Knockdown of DSCAM promotes PANoptosis by inhibiting the activity of the PI3K/AKT pathway. In vivo, DSCAM depletion inhibited tumor growth and enhanced CD8+ T cell infiltration. CONCLUSIONS: The HNSCPAN-index may serve as a potential biomarker for prognostic stratification and prediction of therapeutic responses in HNSCC.