Molecular characteristics of fatty acid metabolic reprogramming in hepatocellular carcinoma and their implications for immunotherapy

Abstract

Aim: Aberrant metabolism represents a hallmark feature of malignancies, which is crucial for facilitating adenosine triphosphate (ATP) production and biosynthesis of macromolecules that sustain cell proliferation, differentiation, and survival. In the context of tumorigenesis, fatty acids (FAs) have garnered substantial attention due to their dual role as secondary messengers and energy substrates. Notably, the pivotal role of FA metabolism in hepatocellular carcinoma (HCC) progression has been extensively explored. Therefore, this study aims to investigate the contributions of FA metabolism in the immunotherapy of HCC, which remain undefined.

Methods: We analyzed messenger RNA expression and genetic alterations of regulators of FA metabolism from public HCC datasets. Based on their FA metabolism profiles, patients were classified into two distinct molecular subtypes: cluster A and cluster B. Using subtype-derived differentially expressed genes, we established an unsupervised FA_score algorithm. Immune infiltration analysis and prognostic screening of 2,484 immune genes were integrated to develop a risk model, ultimately classifying patients into four integrated subtypes: mixed index (MI)-1 to MI-4.

Result: Cluster B exhibited significantly worse overall survival than cluster A. Higher FA_score correlated with shorter survival and increased infiltration of immunosuppressive cells. The MI-2 subgroup showed abundant CD4+ T cells, myeloid-derived suppressor cells, and regulatory T cells, indicating strong immunosuppression and poor prognosis, suggesting limited benefit from immunotherapy.

Conclusion: We developed a novel classification system integrating FA metabolism and immune features. The MI-2 subtype is characterized by immunosuppression and poor outcomes, highlighting the clinical relevance of FA metabolic patterns in shaping the immune microenvironment and guiding personalized treatment in HCC.

Keywords

Hepatocellular carcinoma / fatty acid / metabolism / tumor microenvironment / biomarker

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