Understanding the Tumor Microenvironment and Therapy Resistance in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a group of cancers arising in the oropharyngeal and laryngeal regions. Lifestyle choices such as smoking, tobacco chewing, alcohol consumption, and human papillomavirus (HPV) infection are key risk factors. Therapeutic options include surgical resection, chemoradiotherapy, EGFR-targeting therapy, and immunotherapy. However, the treatments are limited by drug resistance, relapses, and poor response to immunotherapy, especially in advanced diseases. The difference in tissue types and HPV infection status may lead to significant variations in their tumor microenvironment (TME). The heterogeneity contributes to poor treatment response and the development of therapeutic resistance. Therefore, it is critical to have a deeper understanding of the complexities and heterogeneity in TME and its role in treatment resistance. In this review, we focused on tumor heterogeneity and the role of cancer and non-cancer cells in therapeutic resistance. We discussed the studies on human HNSCC, especially HPV-negative, and presented the diversity in the tumor microenvironment and treatment response. Furthermore, we address the existing and experimental therapeutics that target therapy resistance and may lead to a better understanding of the disease and improve therapeutic outcomes.