Abstract
The ERBB receptor family is widely implicated in epithelial malignancies, yet the functional and immunological significance of ERBB3 in head and neck squamous cell carcinoma (HNSCC) remains insufficiently characterized. In this study, we employed single-cell and bulk transcriptomic analyses to comprehensively map the expression patterns and prognostic value of ERBB family members in HNSCC, identifying ERBB3 as a tumor-specific marker predominantly enriched in malignant epithelial clusters. Notably, high ERBB3 expression was paradoxically associated with favorable overall survival, prompting further mechanistic investigation. Functional assays in SCC9 cells demonstrated that ERBB3 promotes proliferation, colony formation, and invasion. Immune profiling revealed that ERBB3-high tumors displayed enhanced communication with B cell subsets, particularly involving immunosuppressive signals such as TNFRSF13B and IL4R. Flow cytometry analysis in a 4NQO-induced mouse model showed that ERBB3 inhibition reduced CCDC50⁺ B cells while restoring MHC-II expression, indicating a shift toward immune activation. These findings highlight a dual role of ERBB3 in HNSCC, acting both as an oncogenic contributor and an immune-modulatory regulator, and position ERBB3 as a promising context-dependent therapeutic target.