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Lipid Metabolism Reprogramming in Tumor-Associated Macrophages Modulates Their Function in Primary Liver Cancers
1
Department of Translational and Clinical Research, Division of Molecular Medicine, Laboratory of Clinical Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
2
Department of Health Sciences, University of Milan, 20142 Milan, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(11), 1858; https://doi.org/10.3390/cancers17111858
Submission received: 24 March 2025
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Revised: 23 May 2025
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Accepted: 30 May 2025
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Published: 31 May 2025
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer 2nd edition)
Simple Summary
Lipids play a key role in the onset, progression, and maintenance of cancers. Lipids from the tumor’s surroundings or synthesized by cancer cells govern many processes that help tumors grow. In addition to supporting tumor development, lipids modify the tumor microenvironment by influencing the recruitment, activation, and function of many immune cells, especially the tumor-associated macrophages. Indeed, macrophages infiltrating the tumor are essential to sustain cancer growth, promoting invasion and mediating immune evasion. This article seeks to review the current research concerning lipid metabolism in the two most frequent primary liver tumors, namely hepatocellular carcinoma and cholangiocarcinoma, focusing on pathways that modify the phenotype and function of tumor-associated macrophages.
Abstract
Lipids are a complex class of biomolecules with pivotal roles in the onset, progression, and maintenance of cancers. Lipids, derived from the tumor microenvironment (TME) or synthesized by cancer cells themselves, govern a large variety of pro-tumorigenic functions. In recent years, lipid metabolism and the reprogramming of liver cancer cells have received increasing attention, revealing that altered regulation of diverse lipid species, including triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol, actively contributes to the initiation and progression of primary liver cancer. Lipid metabolic reprogramming also modifies the TME by influencing the recruitment, activation, and function of immune cells. Tumor-associated macrophages (TAM) are essential components of TME that sustain cancer growth, promoting invasion and mediating immune evasion. Macrophage polarization toward a tumor-supportive phenotype is associated with metabolic reprogramming. Indeed, lipid accumulation and enhanced fatty acid oxidation in TAM contribute to polarization to a M2 phenotype. In this review, we examine lipid metabolism in hepatocellular carcinoma and cholangiocarcinoma, focusing on TAM lipid metabolic reprogramming.
