Unravelling the heterogeneity of oral squamous cell carcinoma by integrative analysis of single‐cell and bulk transcriptome data

Abstract Oral squamous cell carcinoma (OSCC) is a prevalent malignancy of the head and neck with rising global incidence. Despite advances in treatment modalities, OSCC prognosis remains diverse due to the complex molecular and cellular heterogeneity within tumours, as well as the heterogeneity in tumour microenvironment (TME). In this study, we utilized single‐cell RNA sequencing (scRNA‐seq) analysis to explore distinct subpopulations of tumour cells in OSCC tissues and their interaction with components in TME. We identified four major tumour cell subpopulations (C0, C1, C2 and C3) with unique molecular characteristics and functional features. Pathway enrichment analysis revealed that C0 primarily expressed genes involved in extracellular matrix interactions and C1 showed higher proliferation levels, suggesting that the two cell subpopulations exhibited tumour aggressiveness. Conversely, C2 and C3 displayed features associated with keratinization and cornified envelope formation. Accordingly, C0 and C1 subpopulations were associated with shorter overall and disease‐free survival times, while C2 and C3 were weakly correlated with longer survival. Genomic analysis showed that C1 demonstrated a positive correlation with tumour mutation burden. Furthermore, C0 exhibited resistant to cisplatin treatment, while C1 showed more sensitive to cisplatin treatment, indicating that C0 might exhibit more aggressive compared to C1. Additionally, C0 had a higher level of communication with fibroblasts and endothelial cells in TME via integrin‐MAPK signalling, suggesting that the function of C0 was maintained by that pathway. In summary, this study provided critical insights into the molecular and cellular heterogeneity of OSCC, with potential implications for prognosis prediction and personalized therapeutic approaches.