MCT4 drives HCC progression by activating MMPs and polarizing M2 macrophages

Area of Science:

• Oncology
• Cancer Metabolism
• Immunology

Background:

• Hepatocellular carcinoma (HCC) has a poor prognosis, with metabolic reprogramming, especially lactate transport, critical to its progression.
• Monocarboxylate transporter 4 (MCT4), a lactate exporter, is overexpressed in cancers, but its role in HCC pathogenesis and immune modulation is unclear.

Purpose of the Study:

• To investigate the role of Monocarboxylate transporter 4 (MCT4) in hepatocellular carcinoma (HCC) progression and immune microenvironment.
• To identify MCT4 as a potential therapeutic target for HCC.

Main Methods:

• Integrated bioinformatic analysis of HCC datasets (TCGA-LIHC, GSE46408, GSE36411).
• Experimental validation in HCC cell lines and a murine xenograft model.
• Functional assays (wound healing, Transwell invasion, Western blot, flow cytometry) and immune cell analysis (CIBERSORT, single-cell RNA sequencing).

Main Results:

• MCT4 is a prognostic hub gene in HCC, upregulated and linked to poor survival.
• MCT4 expression correlates with matrix metalloproteinase (MMP) pathways, and its knockdown suppresses HCC cell invasion and migration.
• High MCT4 expression is associated with an immunosuppressive tumor microenvironment, characterized by M2 macrophage polarization, which is reversed by MCT4 knockdown in vivo.

Conclusions:

• MCT4 promotes HCC progression via MMP-mediated invasion/metastasis and M2 macrophage polarization.
• MCT4 is a promising therapeutic target for enhancing antitumor immunity and inhibiting metastasis in HCC.