Abstract
Cholesterol metabolism plays a pivotal role in the function and polarization of macrophages, a heterogeneous population of immune cells with diverse roles in cancer progression. This article explores the current understanding of how cholesterol metabolism regulates macrophage-mediated antitumor responses, highlighting potential therapeutic strategies.
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Introduction
Cholesterol metabolism is a complex biological process that involves the synthesis, transport, storage, and degradation of cholesterol within the body. Cholesterol is an essential lipid molecule that serves as a structural component of cell membranes and is a precursor for the synthesis of various hormones, bile acids, and vitamin D.
The majority of cholesterol in the body is synthesized in the liver and intestine, with the liver being the primary site of synthesis. The synthesis of cholesterol begins with the conversion of acetyl-CoA, a by-product of cellular metabolism, into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction is catalyzed by the enzyme HMG-CoA reductase, which is a key regulatory enzyme in cholesterol synthesis.
Once synthesized, cholesterol is transported throughout the body in lipoprotein particles. The main classes of lipoproteins are high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL). HDL particles transport cholesterol from tissues back to the liver for excretion, while LDL and VLDL particles transport cholesterol from the liver to tissues.
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Cholesterol Metabolism in Macrophages
Macrophages rely on cholesterol for membrane biogenesis, signaling, and cytokine production. Cholesterol can be synthesized endogenously or acquired from the environment through scavenger receptors. The balance between cholesterol synthesis and efflux is tightly regulated by various enzymes and transporters, including 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-binding cassette transporters (ABCs).
Role of Cholesterol Metabolism in Macrophage Polarization
Macrophage polarization towards an M1 (classically activated) or M2 (alternatively activated) phenotype is influenced by cholesterol metabolism. M1 macrophages, characterized by high proinflammatory cytokine production, require cholesterol for optimal function. Conversely, M2 macrophages, which promote tumor growth and angiogenesis, are associated with increased cholesterol storage.
Cholesterol Metabolism and Macrophage-Mediated Antitumor Responses
Accumulating evidence suggests that modulating cholesterol metabolism can skew macrophage polarization towards an antitumor phenotype. For instance, inhibiting cholesterol synthesis through HMGCR inhibitors promotes M1 polarization and enhances macrophage-mediated tumor killing. Conversely, stimulating cholesterol efflux by upregulating ABC transporters favors M2 polarization and tumor progression.
Therapeutic Strategies Targeting Cholesterol Metabolism
Several therapeutic strategies targeting cholesterol metabolism in macrophages are being explored for cancer treatment. These include the use of HMGCR inhibitors to promote antitumor M1 polarization, as well as the development of novel drugs that stimulate cholesterol efflux and inhibit tumor-promoting M2 polarization.
Latest Research
On April 19, Wang Hongyan's research group at the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, in collaboration with Shanghai University, Fudan University and Shanghai Jiao Tong University, published an online paper titled 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolism in Immunity. Research paper on reprogramming to educate immunosuppressive macrophages. This study discovered the key cholesterol metabolism enzyme CH25H and metabolite 25-HC that inhibit inflammatory macrophage activation, providing a new metabolic target for tumor immunotherapy targeting macrophages, and proposing a method for reprogramming cholesterol metabolism to regulate innate immunity. gained new insights.
In response to pathogenic microbial infection, macrophages can secrete pro-inflammatory cytokines and interferons to eliminate pathogens. They can respond to the stimulation of the tumor microenvironment or the cytokine IL-4/IL-13 and express anti-inflammatory cytokines and arginase ( Arg1) to consume arginine in the microenvironment and block T cell proliferation and tumor killing functions. Cholesterol metabolites are important components of cell membranes and organelle membranes and can regulate cell proliferation, migration, inflammation and other functions, while cholesterol disorders are associated with a variety of diseases. Earlier, studies found that the accumulation of 7-dehydrocholesterol can promote the production of type I interferon, which is opposite to the function of cholesterol inhibiting interferon. Cholesterol is oxidized to produce 25-hydroxycholesterol (25-HC); in turn, 25-HC is oxidized to produce 7a,25-hydroxycholesterol. 25-HC and 7a,25-hydroxycholesterol are elevated in the peripheral blood of patients with the autoimmune disease systemic lupus erythematosus (SLE). 7a,25-hydroxycholesterol reduces the onset of SLE by binding to and activating the G protein-coupled receptor EBI2 on the surface of macrophages, inhibiting the expression of various chemokines and inflammatory factors. However, how cholesterol metabolism regulates the immunosuppressive functions and molecular mechanisms of tumor-associated macrophages (TAMs) remains unclear.
The team used three types of immunosuppressive macrophages, namely M2 macrophages stimulated by cytokines IL-4 and IL-13, macrophages incubated in conditioned medium of the liver cancer cell line Hepa1-6, and solid tumor tissues. The sorted TAMs were screened for the expression levels of cholesterol metabolism enzymes, and it was found that cholesterol 25-hydroxylase (CH25H) was induced to be highly expressed. Previous studies have confirmed that infection promotes the high expression of CH25H and oxidizes cholesterol to 25-HC, thereby blocking the virus from invading host cells through membrane fusion. This study found increased levels of oxysterol 25-HC in M2 macrophages, TAMs, and tumor tissues. By analyzing published data, scRNA-seq found that CH25H is highly expressed in MARCO+TAMs or LYVE1+TAMs in a variety of solid tumor tissues and is negatively correlated with the prognosis of tumor patients.
Further, studies have found that lactic acid in the tumor microenvironment can induce Ch25h and the cytokine IL-4/IL-13 regulates Ch25h transcription through the transcription factor STAT6. The accumulated 25-HC accumulates in macrophage lysosomes and competes with cholesterol to bind to the lysosome-localized signaling protein GPR155 to inhibit mTORC1 activation. By enhancing the activation of AMPKa, the transcription factor STAT6 is phosphorylated at serine 564 to enhance the transcriptional activity of STAT6 and promote macrophages to produce more Arg1 and anti-inflammatory factors. In macrophages, knocking out Ch25h can reverse the immunosuppressive function of TAM and block the development of various subcutaneous tumors, accompanied by enhanced T cell infiltration and activation and high expression of the immune checkpoint PD-1 in tumor tissues. Therefore, the combination of anti-PD1 monoclonal antibodies can enhance the anti-tumor effect.
In summary, targeting cholesterol oxidase CH25H promotes the transformation of "cold tumors" into "hot tumors" and combines immune checkpoints to improve the efficacy of tumor immunity. The team proposed the concept of locating oxysterols and cholesterol in lysosomes and the mutual balance between the two to regulate macrophage fate. At the same time, they expanded the cholesterol oxidase CH25H and oxysterol 25-HC from the field of infection to the field of tumor immunotherapy.
Conclusion
Cholesterol metabolism plays a fundamental role in regulating macrophage polarization and function in cancer. By targeting cholesterol metabolism, we may be able to harness the antitumor potential of macrophages and develop novel therapeutic strategies for cancer treatment. Future research should focus on elucidating the molecular mechanisms underlying cholesterol-mediated macrophage polarization and exploring the clinical potential of cholesterol metabolism-targeting therapies.