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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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Mohring, V., Ancion, M., Hubert, P., Lardinois, F., Bizet, M., Stern, D., Liegeois, M. A., Roncarati, P., Agirman, F., Maloujahmoum, N., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2026-014841
Verstraete, P., Heylen, E., Sánchez‐Castillo, A., Fontela, J., Matthys, L., Meykens, S., Herranz, Ó., Verma, S., Doan, L. M. T., Aerschot, L. V., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.17.744660
The interplay between lipid metabolism, cancer progression and anti-cancer immunity
Koh, C., Lee, Y., Kim, I., & Chung, Y. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-026-01783-3
Host Immunometabolism and Epigenetic Regulation in Chronic and Recurrent Infectious Diseases
Chow, V. T. K., & Coats, M. T. (2023) · Infectra · doi:10.70945/i.v01i01.006
Sun, J., Lei, Y., Yang, H., Li, S., & Wu, B. (2026) · Science Advances · doi:10.1126/sciadv.aee4337
(2023) · PubMed Central · Cited by 15
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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