Monocarboxylate Transporter 1 (MCT1) in Cancer Biology: Canonical Transport Functions, Metabolic–Epigenetic Crosstalk and Emerging Nuclear Localisation

MCT1 (encoded by SLC16A1) is a key regulator of cellular metabolism, mediating proton-coupled transport of lactate, pyruvate, ketone bodies, and other monocarboxylates across biological membranes. Long recognised for its canonical role in metabolic homeostasis and the lactate shuttle, MCT1 is now implicated in tumour-promoting processes, including metabolic symbiosis, angiogenesis, immune evasion, and therapy resistance. Aberrant plasma membrane MCT1 (PM MCT1) expression is observed in diverse malignancies, where it may carry prognostic or predictive value, making it an attractive therapeutic target. This review integrates established metabolic functions of MCT1 with emerging evidence showing its unexpected nuclear localisation (nMCT1) and potential to modulate chromatin state through metabolite-driven epigenetic regulation. In particular, we discuss how PM MCT1 substrates such as lactate, pyruvate, and ketone bodies may influence histone modifications and gene regulation through direct or indirect metabolic mechanisms. We also examine reports of nuclear or nuclear-associated MCT1 (nMCT1) staining in immune and cancer contexts, while emphasising that functions of nMCT1 remain insufficiently validated. By distinguishing established transport biology from substrate-mediated epigenetic effects, this review highlights both the therapeutic promise of MCT1 targeting and the experimental gaps that must be addressed. We conclude by outlining priorities for future research, including orthogonal validation of putative nMCT1, improved patient stratification based on MCT1 expression and metabolic phenotype, and rational combination strategies for MCT1-directed therapies.