Table 1.

Molecular subtypes of head and neck cancer: characteristics and clinical implications.

Molecular Subtype	Characteristic Features	Clinical Implications	Reference
HPV-positive	Presence of HPV DNA, overexpression of p16 (a surrogate marker for HPV oncogenic activity), and absence of TP53 mutations. Typically associated with oropharyngeal cancers.	HPV-positive tumours respond better to radiation and chemotherapy, and patients have a better overall prognosis. These tumours also have a reduced risk of recurrence compared to HPV-negative tumours.	[20]
Basal	High expression of basal cell markers, frequent EGFR amplification, and TP53 mutations. These tumours often show poor differentiation.	Poor prognosis due to aggressive tumour behaviour and resistance to certain therapies. EGFR inhibitors, like cetuximab, may be used, but overall survival remains low.	[21]
Mesenchymal	Characterized by epithelial-to-mesenchymal transition (EMT), with expression of mesenchymal markers such as vimentin and N-cadherin, and reduced E-cadherin levels.	High resistance to conventional treatments like chemotherapy and radiation therapy. This subtype is typically more invasive and associated with metastatic potential.	[22]
Atypical	Defined by mutations in NOTCH1 and low expression of HPV and p16. Exhibits molecular heterogeneity.	Variable prognosis; potential sensitivity to NOTCH inhibitors in the future. These tumours may benefit from targeted therapies, but their response to current treatments is unpredictable.	[23]
Classical	High expression of genes involved in cell cycle regulation, including cyclin D1 and CDK6, with frequent alterations in TP53.	Highly aggressive with rapid tumour progression. Targeting cell cycle pathways with CDK inhibitors has shown potential for treatment in clinical trials.	[24]
Immune-Related	High levels of immune cell infiltration, particularly lymphocytes, and expression of immune checkpoint molecules like PD-L1.	These tumours show potential responsiveness to immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors like pembrolizumab or nivolumab). Immunotherapy has shown promise in improving survival rates.	[25]
Hypoxic	Overexpression of hypoxia-inducible factors (HIFs), leading to an adaptive response to low oxygen environments. These tumours are typically resistant to apoptosis and have enhanced angiogenesis.	Poor prognosis due to treatment resistance and aggressive progression. Targeting hypoxic pathways and angiogenesis inhibitors may offer therapeutic benefits.	[26]
Metabolic	Characterized by alterations in metabolic pathways, including increased glycolysis (Warburg effect) and overexpression of glucose transporter 1 (GLUT1).	Potential for therapies targeting metabolic pathways (e.g., inhibitors of glycolysis or metabolic enzymes). These tumours may also be resistant to conventional therapies, making metabolic inhibitors a promising approach.	[27]