Monocarboxylate transporter 4 (MCT4) (MCT4)

Monocarboxylate transporter 4 (MCT4), encoded by the SLC16A3 gene, is a proton-coupled symporter that primarily facilitates the efflux of L-lactate and protons from highly glycolytic cells. It is a member of the solute carrier family 16 and the major facilitator superfamily, characterized by 12 transmembrane domains. Under physiological conditions, MCT4 is expressed in tissues with high glycolytic rates, such as white skeletal muscle, astrocytes, and activated macrophages, where it prevents intracellular acidification by removing metabolic byproducts. In the context of oncology, MCT4 is frequently upregulated in response to hypoxia via HIF-1α and is a hallmark of the Warburg effect, allowing cancer cells to maintain high glycolytic flux and survive in acidic microenvironments. High MCT4 expression is associated with poor prognosis, metastasis, and resistance to therapy in various malignancies, including lung, breast, and renal cell carcinomas. Pharmacological inhibition of MCT4 aims to induce intracellular lactic acidosis and metabolic crisis in tumor cells while potentially reversing the immunosuppressive effects of extracellular lactate on T cells. Current therapeutic strategies involve selective small-molecule inhibitors like VB-124 or dual MCT1/4 inhibitors like syrosingopine, often in combination with other metabolic or immune checkpoint inhibitors.

Other names

Solute carrier family 16 member 3SLC16A3MCT 4MCT-4Monocarboxylic acid transporter 4MCT3

Inhibition of lactate efflux leading to intracellular acidification, metabolic stress, and reversal of immunosuppression