Most solid tumors display altered metabolism, notably a strong reliance on lactic acid fermentation despite oxygen availability—a hallmark of cancer. This glycolytic reprogramming leads to extracellular acidification, promoting tumor aggressiveness, increased migration, and therapy resistance. Targeting this metabolic phenotype with glycolytic inhibitors (GIs), such as dichloroacetate (DCA), offers a promising strategy to impair tumor progression and sensitize cancer cells to chemotherapy. This project aims to investigate the effects of DCA on metabolism and multidrug resistance (MDR) in oral cancer cells. Given that conventional therapies often lack specificity and cause systemic toxicity, targeting glycolysis—a key vulnerability of cancer cells—could provide a more selective and effective approach. DCA disrupts energy metabolism, reduces lactate production, and may modulate MDRassociated protein activity by limiting ATP availability. Our goal is to explore the therapeutic potential of DCA in overcoming drug resistance, offering new insights into oral tumor biology and future combination strategies.