The DOI matches its Crossref record; 44 of the 45 references it cites were found in a registry or an index.
Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment
Open accessAbstract
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 were 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 a 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 mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T cell-based immunotherapy.
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“Even though both oxidative and ER stress have been shown to contribute to T cell dysfunction across different tumor types (44-51),”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [44]
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Cites
Cancer immunotherapy using checkpoint blockade
Ribas, A., & Wolchok, J. D. (2018) · Science · doi:10.1126/science.aar4060 · Cited by 6,791
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 13×
“Tumor-infiltrating CD8+ T cells are associated with progressive loss of effector function due to prolonged antigen exposure and a suppressive tumor microenvironment (Wherry, 2011).”
InfluentialCTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition
Buchbinder, E. I., & Desai, A. (2016) · American Journal of Clinical Oncology · doi:10.1097/coc.0000000000000239 · Cited by 2,360 · cited 1×
“, the combination of anti-PD-1 with anti-CTLA-4 (Buchbinder and Desai, 2016; Duraiswamy et al., 2013; Dyck and Mills, 2017), anti-PD-1 with anti-TIM-3 (Sakuishi et al.”
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
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Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway
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Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments
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VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors
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Statin use and reduced cancer-related mortality
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Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism
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Endoplasmic reticulum stress signals in the tumour and its microenvironment
Chen, X., & Cubillos-Ruiz, J. R. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00312-2 · Cited by 1,356
The updated landscape of tumor microenvironment and drug repurposing
Jin, M.-Z., & Jin, W.-L. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00280-x · Cited by 1,262
Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer
Snaebjornsson, M. T., Janaki-Raman, S., & Schulze, A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.010 · Cited by 1,097
Ma, X., Xiao, L., Liu, L., Ye, L., Pan, S., Bi, E., Wang, Q., Yang, M., Qian, J., & Yi, Q. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.015 · Cited by 1,048
Self-citationCD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4
Liao, P., Wang, W., Wang, W., Kryczek, I., Xiong, L., Bian, Y., Sell, A., Wei, S., Grove, S., Johnson, J. K., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.02.003 · Cited by 947
Metadata
- Authors
- Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., Wang, Q., Yang, M., Kalady, M. F., Qian, J., Zhang, A., Gupte, A. A., Hamilton, D. J., Zheng, C., & Yi, Q.
- Affiliations
- Houston Methodist (US)
- Wake Forest University Health Sciences (US)
- Cleveland Clinic (US)
- Houston Methodist Research Institute (US)
- Second Hospital of Shandong University (CN)
- Corresponding author
- Yi, Qing
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 30
- Issue
- 1
- Pages
- 143-156.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7061417
- OpenAlex
- W2941036215
- Cited by
- 1,033
- References
- 45
- Citations by year
- 2026: 176 · 2025: 204 · 2024: 187 · 2023: 169 · 2022: 136 · 2021: 100 · 2020: 47 · 2019: 12
- FWCI
- 31.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- cholesterol, CD8+ T cell exhaustion, tumor microenvironment, immune checkpoint, PD-1, 2B4, TIM-3, LAG-3, endoplasmic reticulum stress, XBP1, adoptive T cell therapy, antitumor immunity, cholesterol metabolism
- MeSH terms
- Animals, Cholesterol, Flow Cytometry, Humans, Immunotherapy, Melanoma, Experimental, Blotting, Western, CD8-Positive T-Lymphocytes, Immunoprecipitation, Mice, Tumor Microenvironment, Real-Time Polymerase Chain Reaction, Programmed Cell Death 1 Receptor
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