Cancer-associated fibroblasts in head and neck tumours: signalling networks and therapeutic implications with insights from vestibular schwannoma

Abstract

Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells that influence extracellular matrix (ECM) organisation, tumour-cell state, immunity, and treatment response in head and neck squamous cell carcinoma (HNSCC). This review synthesises evidence on CAF origins and states and on the transforming growth factor beta (TGF-β), Wnt/β-catenin, PI3K/AKT/mTOR, and Hippo–YAP/TAZ networks that mediate fibroblast interactions with tumour and immune cells. Vestibular schwannoma (VS) is considered only as a hypothesis-generating benign stromal reference: both tumours contain fibroblast and ECM-remodelling compartments, but differ fundamentally in cell of origin, anatomy, oncogenic drivers, immune context, and invasive behaviour. VS stromal fibroblasts are not designated as CAFs unless a study has explicitly applied that term, and cross-tumour observations are not treated as evidence of biological equivalence. Single-cell and spatial studies reveal multiple HNSCC fibroblast states, including myofibroblastic, inflammatory, antigen-presenting and fibroblastic reticular cell (FRC)-like, and immune-regulatory populations, but nomenclature and marker sets remain inconsistent and most inferred functions require perturbational validation. Translational evidence is similarly uneven: broad CAF depletion can be harmful in some non-HNSCC models, whereas pathway- or state-selective modulation is supported mainly by preclinical studies. Early HNSCC trials of TGF-β/programmed death-ligand 1 (PD-L1) blockade and NADPH oxidase 1/4 (NOX1/4) inhibition provide feasibility signals but not definitive efficacy. Current evidence supports biomarker-guided investigation of functionally defined CAF states; stromal observations in VS remain hypothesis-generating and require direct experimental validation.