Metabolic Reprogramming in Oral Cancer: A Narrative Review of Therapeutic Perspectives with Emphasis on...

Oral squamous cell carcinoma (OSCC) represents a significant global health challenge characterized by high morbidity and mortality, frequently driven by therapeutic resistance and tumor aggressiveness. Metabolic reprogramming has emerged as a hallmark of OSCC, enabling tumor cells to sustain proliferation, survive under adverse microenvironmental conditions, and evade therapeutic stress. Recent advances in cancer metabolism have identified metabolic plasticity as a central determinant of OSCC progression and treatment failure, highlighting the need to integrate evidence on metabolic vulnerabilities and therapeutic opportunities. This narrative review aims to provide an updated overview of metabolic reprogramming in OSCC, with particular emphasis on the interplay between glycolysis, mitochondrial metabolism, glutamine metabolism, and fatty acid oxidation, and to discuss how these interconnected pathways may be therapeutically exploited. Although OSCC cells exhibit enhanced aerobic glycolysis, mitochondria remain functionally active and play critical roles in energy production, redox homeostasis, and metabolic adaptation. The therapeutic potential of targeting tumor metabolism is discussed, highlighting dichloroacetate (DCA) as a promising metabolic modulator capable of inhibiting pyruvate dehydrogenase kinase (PDK), restoring mitochondrial glucose oxidation, and partially reversing the glycolytic phenotype. The review also examines the current translational limitations of DCA, including toxicity, pharmacokinetic constraints, and compensatory metabolic adaptations that restrict its efficacy as a standalone therapy. Furthermore, potential synergistic strategies are explored, particularly the combination of DCA with paclitaxel, which enhances therapeutic efficacy through concurrent disruption of cytoskeletal integrity and metabolic homeostasis, thereby increasing cellular susceptibility to apoptosis and overcoming chemoresistance.