Lipid Metabolism Reprogramming in Tumor-Associated Macrophages Modulates Their Function in Primary Liver Cancers

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.

Keywords: cholangiocarcinoma; hepatocellular carcinoma; immunosuppression; lipids; macrophages; metabolism; tumor microenvironment.

Figure 1

Lipid content is highly deregulated in primary liver cancer. The figure summarizes lipid alterations in HCC and iCCA as discussed in the text. BA: bile acids; Cer: ceramides; CHOL: cholesterol; FA: fatty acids; GPL: glycerophospholipids; LPCs: lyso-phosphatidylcholines; MUFA: mono-unsaturated fatty acids; MUFA-PCs: mono-unsaturated fatty acids phosphatidylcholines; PCs: phosphatidylcholines; PUFA: poly-unsaturated fatty acids; S1P: sphingosine -1 phosphate; SFA: saturated fatty acids; SM: sphingomyelins; SPL: sphingolipids; ST: sterols. This presentation was created by BioRender (version 201).

Figure 2

The lipid content and lipid metabolism of tumor cells are profoundly altered in primary liver cancers, perturbing the tumor microenvironment. Recent advances in single-cell and spatial technologies have revealed that macrophages within the tumor microenvironment of primary liver cancers constitute a remarkably heterogeneous population, characterized by diverse phenotypes, multifaceted functions, and a high degree of plasticity. Macrophages are influenced by the exchange of lipids derived from tumor cells, which ultimately promote immunosuppression and tumor progression. This presentation was created by BioRender (version 201).