Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

Xingzhe Ma, Enguang Bi, Yong Lu, Pan Su, Chunjian Huang, Lintao Liu, Qiang Wang, Maojie Yang, Matthew F. Kalady, Jianfei Qian, Aijun Zhang, Anisha A. Gupte, Dale J. Hamilton, Chengyun Zheng, Qing Yi

Research output: Contribution to journalArticlepeer-review

428 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)143-156.e5
JournalCell Metabolism
Issue number1
Early online dateApr 18 2019
StatePublished - Jul 2 2019


  • CD8+ T cells
  • cholesterol
  • exhaustion
  • immune checkpoints
  • tumor microenvironment

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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