Monocarboxylate Transporters (MCTs) in Physiology and Cancer: from Fundamentals to Clinical Translation.

Monocarboxylate transporters (MCTs) are vital to physiological pH regulation, redox balance, and energy homeostasis by mediating proton-coupled transport of lactate and other monocarboxylates across cell membranes. MCT1 and MCT4 are especially important during metabolically demanding states, where they support lactate shuttling between oxidative and glycolytic cells. To sustain rapid growth and biosynthesis, the metabolism of highly proliferative cells, including cancer cells, shifts toward glycolysis with increased lactate production. In this setting, MCTs enable lactate and proton efflux, preventing intracellular acidification and maintaining glycolytic flux. Cancer cells frequently co-opt this system, overexpressing MCT1 and MCT4, which is associated with aggressive behavior, poor prognosis, and treatment resistance. These insights have motivated the development of MCT inhibitors, one of which has entered early clinical evaluation, suggesting potential therapeutic benefit in selected tumors. This review first introduces core aspects of cellular metabolism and then outlines the physiological roles, regulation, and tissue distribution of MCTs in normal tissues. It next examines how MCTs are dysregulated across cancer types to support the glycolytic phenotype, remodel the tumor microenvironment, and drive malignant progression, with particular focus on the prognostic impact of MCT expression. The article summarizes evidence linking MCT overexpression to poor outcomes and therapy resistance, and surveys efforts to therapeutically target MCTs and key translational barriers. Finally, it highlights future directions for exploiting MCT biology in precision oncology.