Noninvasive Characterization of Tumor Heterogeneity in HNSCC: From Clinical Utility to Biological Correlates

ABSTRACT This study employed an imaging‐decoding strategy to quantitatively characterize intratumoral heterogeneity (ITH) in patients with head and neck squamous cell carcinoma (HNSCC), and further evaluated the capacity of the imaging‐based ITH score in prognostic stratification and immunotherapy response prediction. A total of 993 HNSCC patients from three medical centers and one public database were stratified into seven sets. Using an unsupervised radiomics framework integrating local variation and global distribution, tumor regions of interest (ROIs) and volumes of interest (VOIs) were separately analyzed to calculate 2D and 3D ITH scores. The association between the ITH score and patient prognosis was evaluated across independent prognostic sets, and its predictive performance for pathologic complete response (pCR) was assessed in an immunotherapy set. Additionally, histological and molecular characteristics of the ITH score were explored via the pathological set and the genomic set. The ITH score demonstrated robust prognostic value and good predictive performance. Biologically, low‐ITH tumors exhibited a higher proportion of inflammatory and connective cells, and were enriched in immune–related pathways, whereas high‐ITH tumors exhibited increased heterogeneous tumor cells and upregulation of metabolic pathways. The proposed ITH score represented a reliable, noninvasive, and biologically interpretable imaging biomarker that effectively quantified tumor heterogeneity in HNSCC.