Tumour microenvironment diversity of HNSCC and the molecular landscape of recurrent disease

• Immune cells in the tumour microenvironment strongly influence treatment response. • High levels of cytotoxic T lymphocytes are linked to improved overall survival. • PD-1 on tumour-infiltrating T cells is linked with disease progression. • Spatial profiling shows immune cell organisation affects immunotherapy outcomes. • Recurrent disease often shows a cold tumour microenvironment with low immune activity. Head and neck squamous cell carcinoma (HNSCC) represents a biologically diverse group of malignancies within the upper aerodigestive tract and oral cavity and remains a significant cause of global morbidity and mortality. Increasing evidence highlights that the tumour microenvironment (TME) plays a central role in disease progression and therapeutic response. Distinct immune and stromal profiles have been observed between HPV positive (HPV+) and HPV negative (HPV-) HNSCC, underpinning their differing natural history and responses to immunotherapy. Despite advances, only 15–20% of patients with recurrent or metastatic HNSCC (RMHNSCC) respond to immunotherapy, with no difference in response being seen between HPV+ and HPV- disease. This may reflect the complexity and heterogeneity of the TME. This review explores how emerging spatial omics technologies, combining molecular, and spatial context, are reshaping our understanding of the HNSCC microenvironment, with emphasis on recurrent and/or metastatic disease. By delineating the spatial organisation of immune, stromal, and metabolic features, these approaches provide new insights into mechanisms of treatment resistance, prognostic biomarkers, and therapeutic vulnerabilities. Understanding spatial TME dynamics across HPV-related subtypes may ultimately guide more precise and effective treatment strategies for HNSCC.