The fate of immune cells is dictated not only by the extrinsic stimuli they received but is also profoundly governed by their intrinsic metabolic states. Notably, cholesterol metabolism does more than just provide essential "building blocks" for cell membrane biogenesis; it also exerts multifaceted "orchestrating functions" that directly regulate immune cell signaling transduction and functional outputs.
Deciphering how cholesterol metabolism fine-tunes immune responses has emerged as a cornerstone for unveiling the principles governing immune cell fate and function, thereby guiding the design of next-generation immunotherapeutic strategies.
In a study published in Immunity, the research team led by Prof. XU Chenqi from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences/ Hangzhou Institute for Advanced Study, collaborated with the team led by Prof. YANG Wei from the Southern Medical University, Guangzhou and the team led by Prof. WANG Guangchuan from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences was invited to publish a comprehensive review paper titled "Cholesterol metabolism in immune cells: from mechanisms to therapeutic opportunities" in the internationally renowned immunology journal Immunity. This review systematically summarizes the molecular mechanisms by which cholesterol metabolites and metabolic proteins regulate immune cell functions. It outlines how immune cells adopt tailored cholesterol metabolic programs to support their distinct functional demands across various functional states and tissue microenvironments. Furthermore, the review discusses how key physiological and pathological factors modulate immune cell cholesterol metabolism to influence host immune responses, and explores the clinical translation opportunities of targeting cholesterol metabolism to treat cancer, cardiovascular diseases, autoimmune disorders, and infectious diseases. Ultimately, this work serves as a panoramic guide to the field of immune cell cholesterol metabolism.
Immune cell cholesterol metabolism primarily comprises four major pathways, generating multiple classes of cholesterol metabolites that directly regulate immune cell functions. The de novo synthesis pathway: Through the mevalonate pathway, farnesyl pyrophosphate is generated and subsequently converted into desmosterol or 7-dehydrocholesterol via the Bloch or Kandutsch-Russell pathways, respectively, culminating in cholesterol synthesis. This pathway yields an abundance of biologically active cholesterol precursors. The uptake pathway: Immune cells mediate the endocytosis of low-density lipoprotein (LDL) through receptors such as LDLR, SR-A1, and CD36; additionally, certain myeloid cells can directly engulf extracellular lipid debris. The efflux and storage pathway: Cells utilize ABCA1 and ABCG1 transporters to export excess cholesterol, or esterify it into lipid droplets inside the cell via ACAT1. The modification pathway: Cholesterol can be oxidized into various types of oxysterols or sulfated into cholesterol sulfate, both of which possess potent immunoregulatory properties. SREBP2 and LXRα/β serve as the master transcription factors governing these pathways, maintaining cholesterol homeostasis in immune cells.
Within the cell, cholesterol metabolites and metabolic proteins exert diverse and vital regulatory functions: they modulate the physical and chemical properties of the cell membrane; act as ligands or bind directly to various proteins to alter their structures and functions, thereby directly modulating immune cell metabolism and signaling pathways; and furthermore, cholesterol metabolic proteins can perform non-canonical functions to directly dictate immune responses.
Tailored cholesterol metabolic programs in lymphocytes and myeloid cells. As the two primary arms of the immune system, lymphocytes and myeloid cells possess starkly different functional profiles, which are supported by their own tailored cholesterol metabolic programs. Upon activation, lymphocytes undergo rapid proliferation, during which cholesterol generated via the endogenous synthesis pathway is critical for both membrane biogenesis and the facilitation of mTORC signaling.
Conversely, their cholesterol uptake is limited to LDLR mediated LDL endocytosis, which plays a less prominent role than endogenous synthesis during lymphocyte activation. In contrast, myeloid cells, particularly macrophages, boast a wider and more robust array of cholesterol uptake pathways than lymphocytes. In a pro-inflammatory state, macrophages suppress endogenous cholesterol synthesis while further ramping up cholesterol uptake. In a repair state, however, they must efficiently activate cholesterol efflux pathways to export engulfed lipid debris, thereby preserving tissue homeostasis. Consequently, while T cells rely heavily on endogenous cholesterol synthesis to fuel their proliferation and effector functions, macrophages depend more on a finely tuned equilibrium between cholesterol endocytosis and efflux to dictate their pro-inflammatory and reparative responses.
Dysregulated immune cell cholesterol metabolism in diseases and novel therapeutic innovations targeting metabolism. Across a multitude of disease scenarios, the homeostatic balance of cholesterol metabolism in immune cells is frequently disrupted. This dysregulation leads to abnormally heightened or suppressed immune responses, which in turn exacerbates disease progression.
This review specifically highlights four major pathological contexts: cancer, cardiovascular diseases, autoimmune disorders, and infectious diseases. Taking the tumor microenvironment as a prime example, there is a striking disparity in cholesterol distribution among various cell types. Tumor cells and tumor-associated macrophages (TAMs) occupy a large amount of cholesterol, leaving cytolytic CD8+ T cells in a state of cholesterol deprivation, which ultimately drives them into exhaustion state. Furthermore, macrophages can engulf cholesterol from the surrounding environment and shuttle it directly to tumor cells; concurrently, both tumor cells and macrophages produce oxysterols that actively suppress the activities of various anti-tumor immune cells.
Precisely intervening in immune cell cholesterol metabolism to restore its normal function represents a highly promising class of novel therapies. For instance, targeting the cholesterol esterification enzyme ACAT1 has demonstrated multifaceted benefits in oncology.
On one hand, ACAT1 inhibitors directly block the esterification and storage of cholesterol within tumor cells, triggering lipotoxicity due to excessive intracellular cholesterol accumulation, which halts tumor growth and viability. On the other hand, ACAT1 inhibition effectively mobilizes endogenous free cholesterol within cytolytic T cells, empowering them with enhanced TCR signaling and elevated killing capacity. This "killing two birds with one stone" metabolic remodeling strategy offers a brand-new paradigm for cancer immunotherapy.
In the realm of immune cell cholesterol metabolism, the future holds a compelling blend of challenges and opportunities. First, the integration of advanced multi-omics technologies will be pivotal in mapping out the multicellular cholesterol metabolic interaction networks within complex tissues across both spatial and temporal dimensions. Additionally, the intricate regulatory mechanisms through which various physiological and pathological factors govern cholesterol metabolism, such as the gut microbiota, hormones, and circadian rhythms, remain a vast frontier waiting to be fully uncovered. Furthermore, gaining a profound understanding of the dynamic evolution of intracellular cholesterol within immune cells during disease states will pave the way for the development of next-generation therapeutics. By precisely targeting specific immune cell types, these novel drugs aim to maximize clinical efficacy while minimizing disruption to systemic cholesterol homeostasis throughout the body.
Reference: https://www.cell.com/immunity/fulltext/S1074-7613(26)00218-9
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