Background: This article aims to provide a broad overview of the oral squamous cell carcinoma (OSCC) tumor stroma, describing and discussing recent advances in the understanding of different stromal elements and their roles in tumor progression. We also describe potential new therapeutic approaches targeting the stroma.

Methods: A literature review on the role of stromal biomarkers in OSCC was conducted. A narrative overview of current literature was undertaken to synthesize the contexts with elaboration and summary.

Results: The crosstalk between cancer cells and the tumor stroma, a major driver of tumor progression and metastasis, has increasingly been unveiled. This review highlights the tumor-to-stroma ratio (TSR) as a valuable prognostic marker in OSCC, with high stromal content (TSR > 50%) linked to poorer survival. On the other hand, tumor-infiltrating lymphocytes are associated with improved prognosis and longer survival. Furthermore, emerging markers, such as cancer-associated fibroblasts and desmoplastic reactions, play significant roles in promoting tumor invasiveness and resistance to therapy. The review identifies gaps in current evidence and proposes directions for future research to further clarify the prognostic utility of stromal components.

Conclusions: Stromal markers provide valuable prognostic insights into OSCC and could enhance clinical decision-making, emphasizing the complexity of OSCC progression.