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      Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics

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          Abstract

          During the past decade, “membrane lipid therapy”, which involves the regulation of the structure and function of tumor cell plasma membranes, has emerged as a new strategy for cancer treatment. Cholesterol is an important component of the tumor plasma membrane and serves an essential role in tumor initiation and progression. This review elucidates the role of cholesterol in tumorigenesis (including tumor cell proliferation, invasion/metastasis, drug resistance, and immunosuppressive microenvironment) and elaborates on the potential therapeutic targets for tumor treatment by regulating cholesterol. More meaningfully, this review provides an overview of cholesterol-integrated membrane lipid nanotherapeutics for cancer therapy through cholesterol regulation. These strategies include cholesterol biosynthesis interference, cholesterol uptake disruption, cholesterol metabolism regulation, cholesterol depletion, and cholesterol-based combination treatments. In summary, this review demonstrates the tumor nanotherapeutics based on cholesterol regulation, which will provide a reference for the further development of “membrane lipid therapy” for tumors.

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          Cancer nanomedicine: progress, challenges and opportunities

          Jinjun Shi, Philip Kantoff, Richard Wooster … (2016)
          The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a
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            Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

            Xingzhe Ma, Enguang Bi, Yong Lu … (2019)
            Tumor-infiltrating T cells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8 + T-cell expression of immune checkpoints and exhaustion. Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8 + T cells was positively and progressively associated with upregulated T-cell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8 + T cells acquired cholesterol, expressed high levels of immune checkpoints, and became exhausted upon entering tumor. Tumor-culture supernatant or cholesterol induced immune checkpoint expression by increasing endoplasmic reticulum (ER) stress in CD8 + T cells. Consequently, the ER-stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8 + T cells effectively restored antitumor activity. This study reveals a novel mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T-cell based immunotherapy. Tumor-infiltrating T cells often lose their effector function. Ma et al. show that cholesterol in the tumor microenvironment induces CD8 + T-cell exhaustion in an ER-stress-XBP1 dependent manner. Reducing cholesterol or ER stress enhanced CD8 + T-cell anti-tumor function, highlighting therapeutic avenues to improve T-cell based immunotherapy in the clinic.
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              Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

              Binlu Huang, Bao-liang Song, Chenqi Xu (2020)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Nanomedicine
                Journal ID (iso-abbrev): Int J Nanomedicine
                Journal ID (publisher-id): ijn
                Title: International Journal of Nanomedicine
                Publisher: Dove
                ISSN (Print): 1176-9114
                ISSN (Electronic): 1178-2013
                Publication date (Electronic): 01 February 2024
                Publication date Collection: 2024
                Volume: 19
                Pages: 1055-1076
                Affiliations
                [1 ]Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, People’s Republic of China
                [2 ]Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, 310006, People’s Republic of China
                [3 ]Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, 310006, People’s Republic of China
                Author notes
                Correspondence: Weidong Fei; Rong Wang, Email feiweidong@zju.edu.cn; 5521085@zju.edu.cn
                Author information
                http://orcid.org/0000-0002-1491-0588
                http://orcid.org/0000-0002-3844-9837
                Article
                Publisher ID: 439828
                DOI: 10.2147/IJN.S439828
                PMC ID: 10844012
                PubMed ID: 38322754
                SO-VID: b6e603e0-ec77-43f9-bcd9-3aa8c77bc970
                Copyright © © 2024 Wu et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 12 September 2023
                Date accepted : 23 January 2024
                Page count
                Figures: 6, Tables: 2, References: 107, Pages: 22
                Funding
                Funded by: study was financially supported by the National Natural Science Foundation of China;
                Funded by: Zhejiang Provincial Natural Science Foundation Public Welfare Projects of China;
                Funded by: the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission;
                This study was financially supported by the National Natural Science Foundation of China (82103505 and 82071616), the Zhejiang Provincial Natural Science Foundation Public Welfare Projects of China (LTGC23H050001), and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2021RC005).
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: cholesterol,tumor,plasma membrane,nanotherapeutics
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: cholesterol, tumor, plasma membrane, nanotherapeutics

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