Cold, Hot, and Lethal-The Tumour Microenvironment and the Immunology of Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinomas (HNSCCs) represent a diverse group of malignancies, both clinically and biologically, with human papillomavirus (HPV) infection playing a significant role. HPV-positive tumours generally tend to have a better prognosis and are driven by oncoproteins E6 and E7. In contrast, HPV-negative tumours typically have a worse prognosis and are often linked to mutations in tumour suppressor genes. HNSCCs exist within a complex environment known as the tumour microenvironment (TME). The TME includes tumour cells, cancer stem cells (CSCs), cancer-associated fibroblasts (CAFs), immune cells, extracellular matrix (ECM), blood vessels, and various signalling molecules. These components support tumour progression, invasion, metastasis, and resistance to treatment. Intercellular signalling within the TME-mediated by cytokines such as IL-6, TGF-b, and galectins-further promotes tumour growth and systemic effects like cachexia. Notably, the TME shares features with granulation tissue during wound healing, supporting the concept of cancer as a chronic, non-resolving wound. Effective therapy must target not only tumour cells but also the dynamic TME.