Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications
In many cancers, the tumor microenvironment is enriched with cholesterol due to increased biosynthesis and uptake by cancer cells, resulting in the accumulation of cholesterol, cholesterol esters, oxysterols and other metabolites with various functions. These molecules serve as structural components...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1579054/full |
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| author | Francisco Alejandro Lagunas-Rangel Francisco Alejandro Lagunas-Rangel |
| author_facet | Francisco Alejandro Lagunas-Rangel Francisco Alejandro Lagunas-Rangel |
| author_sort | Francisco Alejandro Lagunas-Rangel |
| collection | DOAJ |
| description | In many cancers, the tumor microenvironment is enriched with cholesterol due to increased biosynthesis and uptake by cancer cells, resulting in the accumulation of cholesterol, cholesterol esters, oxysterols and other metabolites with various functions. These molecules serve as structural components, energy sources and intracellular signaling mediators, while their toxic by-products are secreted to suppress anti-tumor immune activity and prevent lipid peroxidation that could induce cancer cell apoptosis. Immune cells in the tumor microenvironment also contribute to cholesterol dynamics. Tumor-associated macrophages (TAMs) release cholesterol to support tumor cell metabolism, while myeloid-derived suppressor cells (MDSCs) also release cholesterol and consume essential metabolites such as L-arginine, which impairs T-cell proliferation and activation. Elevated cholesterol in dendritic cells impairs migration and tumor antigen presentation and, in lymphocytes, favors the development of a regulatory T cells (Treg) phenotype and inhibits the release of antitumor cytokines, further weakening the immune response. These findings suggest that targeting cholesterol metabolism is a promising strategy for cancer treatment, improving the efficacy of immune checkpoint blockade (ICB) therapies. In this manuscript, the molecular mechanisms underlying the effects of cholesterol on the tumor immune landscape are reviewed and the potential of cholesterol-lowering drugs to enhance antitumor immune responses is explored. |
| format | Article |
| id | doaj-art-e2e995bd93b34507bf129b5726ac44a3 |
| institution | OA Journals |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-e2e995bd93b34507bf129b5726ac44a32025-08-20T02:16:29ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-04-011510.3389/fonc.2025.15790541579054Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implicationsFrancisco Alejandro Lagunas-Rangel0Francisco Alejandro Lagunas-Rangel1Department of Surgical Sciences, Uppsala University, Uppsala, SwedenLaboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, LatviaIn many cancers, the tumor microenvironment is enriched with cholesterol due to increased biosynthesis and uptake by cancer cells, resulting in the accumulation of cholesterol, cholesterol esters, oxysterols and other metabolites with various functions. These molecules serve as structural components, energy sources and intracellular signaling mediators, while their toxic by-products are secreted to suppress anti-tumor immune activity and prevent lipid peroxidation that could induce cancer cell apoptosis. Immune cells in the tumor microenvironment also contribute to cholesterol dynamics. Tumor-associated macrophages (TAMs) release cholesterol to support tumor cell metabolism, while myeloid-derived suppressor cells (MDSCs) also release cholesterol and consume essential metabolites such as L-arginine, which impairs T-cell proliferation and activation. Elevated cholesterol in dendritic cells impairs migration and tumor antigen presentation and, in lymphocytes, favors the development of a regulatory T cells (Treg) phenotype and inhibits the release of antitumor cytokines, further weakening the immune response. These findings suggest that targeting cholesterol metabolism is a promising strategy for cancer treatment, improving the efficacy of immune checkpoint blockade (ICB) therapies. In this manuscript, the molecular mechanisms underlying the effects of cholesterol on the tumor immune landscape are reviewed and the potential of cholesterol-lowering drugs to enhance antitumor immune responses is explored.https://www.frontiersin.org/articles/10.3389/fonc.2025.1579054/fullSREBP2LXRLDLRmyeloid-derived suppressor cellstumor-associated macrophagesstatins |
| spellingShingle | Francisco Alejandro Lagunas-Rangel Francisco Alejandro Lagunas-Rangel Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications Frontiers in Oncology SREBP2 LXR LDLR myeloid-derived suppressor cells tumor-associated macrophages statins |
| title | Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications |
| title_full | Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications |
| title_fullStr | Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications |
| title_full_unstemmed | Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications |
| title_short | Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications |
| title_sort | cholesterol effects on the tumor immune microenvironment from fundamental concepts to mechanisms and implications |
| topic | SREBP2 LXR LDLR myeloid-derived suppressor cells tumor-associated macrophages statins |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1579054/full |
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