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Cited by 6Cancer, Lipids, and MetabolismCholesterol and Lipid MetabolismSphingolipid Metabolism and Signaling

Role of Protein Regulators of Cholesterol Homeostasis in Immune Modulation and Cancer Pathophysiology

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Wang, Yu, Bendre, Shruti V, Krauklis, Steven A, Steelman, Andrew J, Nelson, Erik R·2025·Endocrinology
DOI 10.1210/endocr/bqaf031PMC PMC11878532
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Abstract

Cholesterol metabolism and homeostasis have emerged as important factors governing various aspects of cancer biology. Clinical associations between circulating cholesterol and poor prognosis or use of cholesterol-lowering medication and improved prognosis have been noted for several different solid tumors. Mechanistically, cholesterol has many different direct and indirect effects on cancer cells themselves but is also critically involved in shaping the function of other cells of the tumor microenvironment, especially immune cells. There are 2 major feedback loops regulating cholesterol homeostasis. Here we highlight the major proteins involved in the so-called oxysterol–bile acid feedback loop and discuss how each has been implicated in cancer biology. We focus on roles within the immune system with implications for cancer. Given that many of these proteins are enzymes or nuclear receptors, both of which are amenable to small molecule intervention, we posit that this axis may represent a promising area for therapeutic intervention.

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Crossref · 10.1210/endocr/bqaf031

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  • Highly immune suppressive myeloid cells such as macrophages are one factor driving resistance to immune therapy.

    “One factor driving resistance is highly immune suppressive myeloid cells (MCs) such as macrophages.”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [4]

    The paper’s discussion of myeloid cells (indexed as Abstract; page unavailable) says they can acquire an immune-suppressive phenotype that reduces T-cell expansion, and it describes macrophage-dependent effects on anticancer immunity. Its discussion of immune checkpoint blockade links tumor NR0B2 expression with treatment response, but does not establish that suppressive macrophages drive resistance to immune therapy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • ABCA1 is a protein involved in cholesterol efflux and translocation from the inner leaflet to the outer leaflet of the plasma membrane.

    “we identified ABCA1, a protein involved in cholesterol efflux and translocation from the inner leaflet to the outer leaflet of the plasma membrane (4, 27).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [4]

    The passage on ABCA1 and reverse cholesterol transport says ABCA1 transports cellular cholesterol to apolipoproteins at the cell surface, supporting its role in cholesterol efflux. Another passage says it shuttles cholesterol from the cytoplasm to the cell surface. Neither passage specifies translocation from the inner to the outer leaflet of the plasma membrane. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Cholesterol and regulators of its homeostasis are important modulators of tumor immunology.

    “Cholesterol and regulators of its homeostasis have emerged as important modulators of tumor immunology (4, 5).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [4]

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Authors
Wang, Y., Bendre, S. V., Krauklis, S. A., Steelman, A. J., & Nelson, E. R.
Affiliations
University of Illinois Urbana-Champaign (US)
Corresponding author
Nelson, Erik R
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2025-02-14
Volume
166
Issue
4
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endocr/bqaf031
PMC
PMC11878532
OpenAlex
W4407574536
Cited by
6
References
12
Citations by year
2026: 4 · 2025: 2
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • Department of Defense Era of Hope Scholar (BC200206, W81XWH-20-BCRP-EOHS)
  • National Institutes of Health (R01 CA288207)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords
cholesterol homeostasis, cholesterol metabolism, oxysterols, bile acids, tumor immunology, tumor microenvironment, immune cells, nuclear receptors, cholesterol-lowering drugs, cancer prognosis, small molecule drugs
MeSH terms
Oxysterols, Animals, Bile Acids and Salts, Cholesterol, Homeostasis, Humans, Immune System, Neoplasms, Tumor Microenvironment

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