[18F]FDG PET/CT multiomics identifies Hedgehog-driven HPV-negative head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with limited predictive markers to guide personalized treatment, particularly in human papillomavirus (HPV)-negative cases, which exhibit poor outcomes. Identifying reliable biomarkers for prognosis and therapeutic response remains a critical challenge. In a retrospective cohort of 51 patients with primary HPV-negative HNSCC, we investigated the prognostic significance of the Hedgehog (HH) signaling pathway and its association with imaging biomarkers. Genomic and transcriptomic analysis revealed that HH pathway activation correlated with distinct [18F]FDG PET/CT radiomic features, notably the PET-derived “histogram:ih.max” - a surrogate for peak [18F]FDG uptake and was associated with inferior survival outcomes. Functionally, pharmacologic inhibition of HH signaling demonstrated anticancer efficacy across multiple models, including HNSCC cell lines, patient-derived tumoroids, and in vivo xenograft models. Importantly, HH inhibition altered imaging characteristics in HNSCC xenografts, leading to a measurable reduction in [18F]FDG uptake. This imaging phenotype closely mirrored our clinical findings, suggesting that [18F]FDG PET/CT radiomics may serve as a non-invasive biomarker to identify and monitor HH-driven HNSCC tumors. The integration of multi-level molecular profiling and functional imaging supports a potential precision oncology strategy, in which HH inhibition may offer a viable therapeutic approach for HPV-negative HNSCC. Our study underscores the value of [18F]FDG PET/CT multiomics in linking tumor biology with imaging features, paving the way for improved patient stratification and treatment monitoring. These findings provide a compelling rationale for further investigation into HH-targeted therapies in this aggressive subset of HNSCC and their clinical implications.