The Role of Cholesterol Metabolism and Its Regulation in Tumor Development

Sep 23, 2026

Uploaded by Rowan

Within the tumor microenvironment, tumor cells undergo metabolic reprogramming of cholesterol driven by intrinsic cellular alterations and extracellular niche changes. Cholesterol reprogramming reshapes the immune landscape, enabling immune evasion and supporting tumorigenesis. Multiple cholesterol uptake and synthesis enzymes are implicated, including NPC1L1, SREBP, HMGCR, SQLE, and PCSK9. This review synthesizes mechanisms linking dysregulated cholesterol metabolism to immune-cell behavior and highlights therapies targeting this pathway to suppress tumor growth and enhance antitumor immunity.

LanguageEnglish

CategoryHealthcare

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Abstract

Introduction

Cholesterol homeostasis and tumor-associated roles

Review scope: mechanisms and therapeutic advances

Cancer Medicine | REVIEW OPEN ACCESS
The Role of Cholesterol Metabolism and Its Regulation in Tumor Development
Yongmei Wu1 | Wenqian Song1 | Min Su1,2 | Jing He3 | Rong Hu1,3 | Youbo Zhao1,2
1Department of Human Histology and Embryology, Guizhou Medical University, Guiyang, Guizhou, China | 2Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China | 3Characteristic Key Laboratory of Translational Medicine Research of Cardiovascular and Cerebrovascular Diseases in Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China
Correspondence: Rong Hu ([hurong@gmc.edu.cn](hurong@gmc.edu.cn)) | Youbo Zhao ([zhaoyoubo@gmc.edu.cn](zhaoyoubo@gmc.edu.cn))
Received: 28 October 2024 | Revised: 27 February 2025 | Accepted: 8 March 2025
Funding: This work was financially supported by the National Natural Science Foundation of China (82203871, 32260165, 82060151, 82160151, 82171343); the Key Laboratory for Research on Autoimmune Diseases of Higher Education schools in Guizhou Province (Qianjiaoji[2023]016); The Science and Technology Foundation of Guizhou Province to Min Su (Qiankehezhicheng[2020]4Y230); The project funded by the China Postdoctoral Science Foundation (2022M720928); and Guizhou Provincial Science and Technology Projects (zk(2022)-404,(2024)-89) .
Keywords: cancer | cholesterol | immune | metabolism | tumor microenvironment | | | --- | --- | | ABSTRACT
Background: Within the tumor microenvironment, tumor cells undergo metabolic reprogramming of cholesterol due to intrinsic cellular alterations and changes in the extracellular milieu. Furthermore, cholesterol reprogramming within this microenvironment influences the immune landscape of tumors, facilitating immune evasion and consequently promoting tumorigenesis. These biological changes involve modifications in numerous enzymes associated with cholesterol uptake and synthesis, including NPC1L1, SREBP, HMGCR, SQLE, and PCSK9.
Review: This review systematically summarizes the role of cholesterol metabolism and its associated enzymes in cancer progression, examines the mechanisms through which dysregulation of cholesterol metabolism affects immune cells within the tumor microenvironment, and discusses recent advancements in cancer therapies that target cholesterol metabolism. Conclusion: Targeting cholesterol metabolism-related enzymes can inhibit tumor growth, reshape immune landscapes, and rejuvenate antitumor immunity, offering potential therapeutic avenues in cancer treatment. | | | 1 | Introduction | membrane and activating specific receptors, including steroids, hydroxycholesterol, and bile acid-oxygenated metabolites [2] . | | Cholesterol, a derivative of cyclopentane polyhydrophenan- | | | threne with the chemical formula C27H46O, is the primary ste- | Cellular cholesterol homeostasis is meticulously regulated through | | roid compound in mammals and plays a critical role in essential | an intricate network that controls its synthesis, absorption, ex- | | cellular processes [1] . As a crucial lipid component of mam- | port, conversion, esterification, storage, and systemic distribution | | malian cell membranes, cholesterol helps maintain membrane | [3]. More importantly, cholesterol and its metabolites play pivotal | | integrity and fluidity, while also contributing to the formation | roles in both promoting tumorigenesis and suppressing anti-tumor | | of membrane microstructures. Moreover, it acts as a key regu- | immune responses. For instance, the deletion of the gene encod- | | lator in cellular signaling by directly interacting with the cell | ing SREBP cleavage-activating protein (SCAP) in the liver leads | | Yongmei Wu and Wenqian Song contributed equally to this work. | | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproducti

FAQs

How does cholesterol metabolism change in the tumor microenvironment?

Tumor cells exhibit metabolic reprogramming of cholesterol due to intrinsic cellular alterations and changes in the extracellular milieu. This alters cholesterol availability and downstream signaling.

Which enzymes are highlighted as key regulators of cholesterol reprogramming in tumors?

The review specifically discusses enzymes and factors involved in cholesterol uptake and synthesis, including NPC1L1, SREBP, HMGCR, SQLE, and PCSK9.

How does targeting cholesterol metabolism relate to cancer therapy?

Targeting cholesterol metabolism-related enzymes can inhibit tumor growth, reshape immune landscapes, and rejuvenate antitumor immunity, offering potential therapeutic avenues.

Sep 23, 2026

Uploaded by Rowan