Slc16a4, also known as monocarboxylate transporter 4 (MCT4), is a key transporter involved in the transmembrane movement of lactate. It plays a crucial role in maintaining intracellular pH homeostasis and is implicated in various metabolic pathways. Its function is vital for normal physiological processes as well as in disease-related metabolic rewiring. Genetic models, such as knockout (KO) mouse models, have been instrumental in understanding its role [3].

In cancer, MCT4-dependent lactate secretion in LKB1-deficient lung adenocarcinoma suppresses antitumor immunity. MCT4 knockout in syngeneic murine models reverses the resistance to PD-1 blockade induced by LKB1 loss, highlighting its role in immunotherapy resistance [1]. In hepatocellular carcinoma, genetic or pharmacological inhibition of MCT4 using VB124 suppresses tumor growth in immunocompetent mice by enhancing CD8+ T cell infiltration and cytotoxicity [4]. In the context of heart failure, a novel MCT4 inhibitor mitigated hypertrophy in cultured cardiomyocytes and in mice, indicating its role in cardiac hypertrophy and failure [2]. In type 2 diabetes-related cardiomyopathy, inhibiting MCT4 alleviates myocardial oxidative stress and pathological damage in diabetic mice [5].

In summary, Slc16a4 (MCT4) is essential for lactate transport and is involved in multiple biological processes and disease conditions. KO/CKO mouse models have been crucial in revealing its role in cancer immunotherapy resistance, cardiac hypertrophy, and diabetic cardiomyopathy, providing potential therapeutic targets for these diseases.