Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics?

As a result of metabolic reprogramming, cancer cells display high rates of glycolysis, causing an excess pro-duction of lactate along with an increase in extracellular acidity. Proton-linked monocarboxylate transporters (MCTs) are crucial in the maintenance of this metabolic phenotype, by mediating the proton-coupled lactate flux across cell membranes, also contributing to cancer cell pH regulation. Among the proteins codified by the SLC16 gene family, MCT1 and MCT4 isoforms are the most explored in cancers, being overexpressed in many cancer types, from solid tumours to haematological malignancies. Similarly to what occurs in particular physiological settings, MCT1 and MCT4 are able to mediate lactate shuttles among cancer cells, and also between cancer and stromal cells in the tumour microenvironment. This form of metabolic cooperation is responsible for important cancer aggressiveness features, such as cell proliferation, survival, angiogenesis, migration, invasion, metastasis, immune tolerance and therapy resistance. The growing understanding of MCT functions and regulation is of-fering a new path to the design of novel inhibitors that can be foreseen in clinical practices. This review provides an overview of the role of MCT isoforms in cancer and summarizes the recent advances in their pharmacological targeting, highlighting the potential of new potent and selective MCT1 and/or MCT4 inhibitors in cancer ther-apeutics, and anticipating its inclusion in clinical practice.

Automated summary

Due to metabolic reprogramming, cancer cells exhibit high levels of glycolysis, resulting in excessive lactate production and increased extracellular acidity. Proton-linked monocarboxylate transporters (MCTs) play a crucial role in maintaining this metabolic phenotype by facilitating the transport of lactate across cell membranes and regulating cancer cell pH. MCT1 and MCT4 isoforms, encoded by the SLC16 gene family, are extensively studied in various cancers and are found to be overexpressed. These isoforms mediate lactate shuttling between cancer cells and also between cancer and stromal cells in the tumor microenvironment, contributing to cancer aggressiveness and therapy resistance. Understanding the functions and regulation of MCTs offers potential for the development of novel inhibitors for clinical application.