Glycolytic Reprogramming in Oral Squamous Cell Carcinoma: Molecular Regulators and Natural Product-Based Therapies

Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, poses significant clinical challenges owing to late-stage diagnosis, frequent recurrence, and therapy resistance. Metabolic reprogramming, particularly the upregulation of aerobic glycolysis, is intricately associated with tumor progression, metastasis, and therapeutic failure. This metabolic alteration not only favors rapid cancer cell proliferation and promotes immune evasion but also results in the formation of a supportive tumor microenvironment (TME). This review synthesizes the current knowledge on the molecular regulators of glycolytic reprogramming in OSCC and elucidates their underlying mechanisms. We also delineated the glycolytic landscape of the OSCC tumor microenvironment, which encompasses cancer-associated fibroblasts (CAFs), CD4⁺ and CD8⁺ T cells, and tumor-associated macrophages (TAMs). Furthermore, we underscore the therapeutic potential of natural product-based strategies that target aerobic glycolysis in OSCC. A deeper understanding of these metabolic pathways may aid in the development of metabolism-targeted interventions for OSCC. This review also offers insights into how targeting glycolytic reprogramming, particularly with natural products, may enhance the efficacy of current chemotherapeutic and immunotherapeutic strategies for OSCC by overcoming resistance and reprogramming the TME.