Zeaxanthin augments CD8+ effector T cell function and immunotherapy efficacy

  • Cell Rep Med. 2025 Sep 16;6(9):102324. doi: 10.1016/j.xcrm.2025.102324.
Freya Q Zhang  1 ,  Jiacheng Li  1 ,  Rukang Zhang  1 ,  Jiayi Tu  1 ,  Zhicheng Xie  1 ,  Takemasa Tsuji  2 ,  Hardik Shah  1 ,  Matthew O Ross  3 ,  Ruitu Lyu  3 ,  Junko Matsuzaki  2 ,  Anna Tabor  2 ,  Kelly Xue  1 ,  Fatima Choudhry  4 ,  Chunzhao Yin  1 ,  Hamed R Youshanlouei  1 ,  Syed Shah  1 ,  Michael W Drazer  1 ,  Yu-Ying He  1 ,  B Marc Bissonnette  1 ,  Yuancheng Li  5 ,  Hui Mao  5 ,  Jun Huang  6 ,  Lei Dong  7 ,  Rui Su  8 ,  Chuan He  3 ,  Kunle Odunsi  2 ,  Jing Chen  9 ,  Hao Fan  10
Affiliations
  • 1. Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
  • 2. Department of Obstetrics & Gynecology, The University of Chicago, Chicago, IL 60637, USA.
  • 3. Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
  • 4. Health Science, DePaul University, Chicago, IL 60614, USA.
  • 5. Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 6. Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA.
  • 7. University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8. Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
  • 9. Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 10. Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
PMID: 40897177 DOI: 10.1016/j.xcrm.2025.102324
Abstract

The detailed mechanisms underlying the regulatory significance of dietary components in modulating anti-tumor immunity remain largely unknown. Here, we apply a co-culture-based screening approach using a blood nutrient compound library and identify zeaxanthin (ZEA), a dietary carotenoid pigment found in many fruits and vegetables and known for its role in eye health, as an immunomodulator that enhances the cytotoxicity of CD8+ T cells against tumor cells. Oral supplementation with ZEA, but not its structural isomer lutein (LUT), enhances anti-tumor immunity in vivo. Integrated multi-omics mechanistic studies reveal that ZEA promotes T cell receptor (TCR) stimulation on the CD8+ T cell surface, leading to improved intracellular TCR signaling for effector T cell function. Hence, ZEA treatment augments the efficacy of anti-PD1 immune checkpoint inhibitor in vivo and the cytotoxicity of human TCR gene-engineered CD8+ T cells in vitro. Our findings uncover a previously unknown immunoregulatory function of ZEA, which has translational potential as a dietary element in bolstering immunotherapy.

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