SLC16A3 links tumor metabolism to therapeutic opportunities in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains one of the most common and lethal malignancies worldwide. Despite advances in diagnostic techniques and therapeutic approaches, the prognosis of patients with advanced HCC is still poor because of high rates of recurrence, metastasis, and therapeutic resistance. Increasing evidence indicates that metabolic reprogramming is a hallmark of HCC progression and plays a critical role in shaping the tumor microenvironment. Among the key regulators of tumor metabolism, solute carrier family 16 member 3 (SLC16A3), also known as monocarboxylate transporter 4 (MCT4), has attracted considerable attention. SLC16A3 is frequently overexpressed in a variety of human cancers, and its elevated expression has been consistently associated with aggressive tumor behavior and unfavorable clinical outcomes. In this review, we comprehensively summarize the current evidence regarding the biological functions of SLC16A3 in cancer, with particular emphasis on its contribution to HCC progression. We discuss the molecular mechanisms and signaling pathways through which SLC16A3 regulates tumor metabolism, proliferation, invasion, metastasis, immune modulation, and resistance to therapy. We also highlight the clinical significance of SLC16A3 as a prognostic biomarker and a potential therapeutic target. Collectively, these findings provide a broader understanding of the role of SLC16A3 in HCC and offer valuable perspectives for the development of more effective targeted therapeutic strategies to improve patient outcomes.