PCSK9 Manipulates Lipid Metabolism and the Immune Microenvironment in Cancer

Abstract

Cancer remains the foremost cause of mortality on a global scale. Immunotherapy has yielded remarkable outcomes in the fight against cancer and is regarded as one of the most crucial and promising therapeutic modalities. PCSK9, a critical target for plasma lipids control, has been extensively and deeply studied in multiple diseases. Currently, the functions of PCSK9 in cancer, particularly its immunomodulatory role, have been progressively revealed. PCSK9 is capable of modulating a variety of immune response throughout tumor progression by orchestrating lipid metabolism. Moreover, PCSK9 governs the cell fate of diverse immune cells, such as inflammatory factor signals, MHC signals, and TCR signals. This review comprehensively summarizes the current state of knowledge regarding the role and underlying mechanisms of PCSK9 in tumorigenesis, progression, immune escape, and drug resistance.

Keywords: PCSK9; cancer; immunotherapy; lipid metabolism.

Figure 1

The mechanism by which PCSK9 regulates lipid metabolism. The level of PCSK9 on the cell surface is influenced by blood cholesterol levels. After undergoing maturation through Golgi modifications, PCSK9 becomes active on the cell membrane surface. It then binds to the low-density lipoprotein receptor (LDLR) and facilitates its degradation via lysosomal pathways. Additionally, PCSK9 plays a role in modulating the expression of SREBP-2, ApoER2, and HMG-CoA reductase, thereby impacting the accumulation of lipids within cells.

Figure 2

The role of PCSK9 in the immune response. The role of PCSK9 in the immune response influences the immune response in the tumor microenvironment and the differentiation, antigen presentation and killing ability of a variety of immune cells by interacting with many lipid metabolism-related molecules and inflammatory factors.

Figure 3

Mechanisms of the regulatory effects of PCSK9 in T cells and tumor cells. The binding of PCSK9 to LDLR impedes the recycling of LDLR and TCR back to the plasma membrane, consequently suppressing the effector function of cytotoxic T cells. By physically associating with MHC-I, PCSK9 instigates lysosomal degradation within tumor cells, which in turn diminishes the surface presentation of MHC-I, thereby facilitating tumor immune evasion. Moreover, PCSK9 triggers an increase in intracellular cholesterol levels, culminating in lipid accumulation within macrophages. PCSK9 modulates the activation of cytotoxic T cells via MAPK-mediated activation of NFATc1. Certain treatments can prevent T-cell apoptosis and promote T-cell survival through the PI3K/Akt pathway. Conversely, PCSK9 can promote apoptosis by inhibiting the PI3K/Akt pathway. PCSK9 drives Th cell differentiation by activating the NF-κB signaling pathway. Additionally, PCSK9 augments vascular inflammation and promotes Th cell differentiation by upregulating or activating the TLR-4/NF-κB pathway. Finally, PCSK9 facilitates the expansion of Tregs through the JAK/STAT pathway.