Unraveling the impact of cancer-associated fibroblasts on lymphatic metastasis of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high incidence of lymphatic metastasis and poor clinical prognosis. Cancer-associated fibroblasts (CAFs), as major component of the tumor stroma, play pivotal roles in shaping the tumor microenvironment. With recent advances of single-cell omics and spatial transcriptomics, increasing evidence has revealed the phenotypic and functional heterogeneity of CAFs and their dynamic interactions with both tumor and stromal cells. These interactions contribute significantly to lymphatic metastasis through promoting lymphangiogenesis, remodeling the extracellular matrix (ECM), and modulating immune responses. Despite the growing recognition of CAFs as key mediators of metastasis, the precise mechanisms through which CAFs drive lymphatic spread in HNSCC remain largely unknown. This gap hampers the development of effective therapeutic strategies specifically targeting CAF-driven lymphatic dissemination. This review comprehensively summarizes the current knowledge on the mechanistic roles of CAFs in lymphatic metastasis in HNSCC, encompassing lymphangiogenesis, pre-metastatic niche formation, lymph node metastasis (LNM), and extranodal extension (ENE). Furthermore, we discuss emerging therapeutic strategies targeting CAFs in other malignant tumors and their translational potential implications for mitigating lymphatic metastasis in HNSCC. Understanding the complex interactions between CAFs and the lymphatic metastatic cascade may provide new opportunities for developing targeted interventions to improve clinical outcomes in HNSCC.