Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting

The role of the tumour microenvironement (TME) in cancer progression and resistance to therapies is now widely recognized. The most prominent non-immune cell type in the microenvironment of oral cancer (OSCC) is cancer-associated fibroblasts (CAF). Although CAF are a poorly characterised and heterogenous cell population, those with an activated myofibroblastic phenotype have been shown to support OSCC progression, promoting growth, invasion and numerous other hallmarks of malignancy. CAF also confer broad resistance to different types of therapy, including chemo/radiotherapy and EGFR inhibitors; consistent with this, CAF-rich OSCC are associated with poor prognosis. In recent years, much CAF research has focused on their immunological role in the tumour microenvironment, showing that CAF shield tumours from immune attack through multiple mechanisms, and particularly on their role in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors, an exciting development for the treatment of recurrent/metastatic oral cancer, but which fails in most patients. This review summarises our current understanding of CAF subtypes and function in OSCC and discusses the potential for targeting these cells therapeutically.

Automated summary

The role of cancer-associated fibroblasts (CAF) in the microenvironment of oral cancer (OSCC) is crucial for promoting cancer progression and resistance to therapy. CAF with an activated myofibroblastic phenotype support OSCC progression and confer resistance to immuno- and targeted therapies, leading to poor prognosis in CAF-rich OSCC. Additionally, CAF shield tumors from immune attack through multiple mechanisms, particularly in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors.