Abstract
The tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous cellular landscape in which cancer cells, stromal cells, immune cells, and their secreted mediators collectively sustain a dynamic ecosystem. Cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) cooperatively shape a desmoplastic stroma that drives resistance mechanisms and facilitates tumor metastasis. As central orchestrators of stromal remodeling, CAFs release cytokines, growth factors, and ECM-modifying enzymes that structurally and functionally alter the tumor niche. Concurrently, aberrantly crosslinked ECM components generate a mechanically rigid stroma that impedes drug penetration and restricts immune cell infiltration. This CAF-ECM axis not only sustains tumor progression but actively engages multiple resistance pathways that limit the efficacy of conventional therapies. A systematic literature search was conducted to identify studies reporting detailed mechanistic findings and translational relevance. Selective inhibitors targeting CAF-derived signaling pathways have shown capacity to suppress HNSCC progression, while ECM-directed interventions appear to improve drug delivery and attenuate tumor advancement. Engineered nanomaterials, evaluated in preclinical models, offer an additional layer of therapeutic precision by enhancing drug distribution within the stroma. Anti-fibrotic agents and immunomodulators have shown potential to disrupt CAF-ECM crosstalk and restore tumor sensitivity to standard anticancer regimens. Collectively, preclinical evidence supports the feasibility of stroma-targeted strategies in HNSCC and points toward combinatorial modalities and stromal reprogramming as clinically meaningful directions for future investigation.