Impact of metabolic reprogramming on the immune response in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignancy worldwide and is characterized by a low rate of early detection. In recent years, immune checkpoint inhibitors (ICIs) have been increasingly incorporated into the management of advanced HCC. However, overall response rates remain modest, indicating that immune checkpoint blockade alone is insufficient to overcome the intrinsic immunosuppressive state of HCC. Advances in metabolomics have provided new insights into early detection and therapeutic response evaluation in HCC and have underscored the functional significance of tumor metabolism in disease progression. The metabolic landscape of the HCC tumor microenvironment is predominantly shaped by alterations in glucose, lipid, and amino acid metabolism. These pathways not only support tumor cell energy production and biosynthetic demands but also reprogram local nutrient availability and metabolite composition, thereby continuously reshaping the immune milieu. This metabolic remodeling impairs effector immune cell function and facilitates the establishment and maintenance of immunosuppressive cell populations. Accordingly, this review summarizes the role of metabolic reprogramming in tumor immune regulation during HCC development, with a focus on the heterogeneity of metabolic reprogramming and immune regulation across distinct etiological backgrounds. Systematic elucidation of immunometabolic crosstalk may enhance the precision and translational potential of combination therapeutic strategies.

Keywords

Hepatocellular carcinoma / metabolic reprogramming / tumor microenvironment / glucose metabolism / lipid metabolism / amino acid metabolism

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