CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy PMID: 31043744

Target-related Cytokines

2026-09-23

CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy

Nature. 2019 May;569(7755):270-274. doi: 10.1038/s41586-019-1170-y.

Weimin Wang ¹ ² , Michael Green ² ³ , Jae Eun Choi ² ⁴ ⁵ , Miguel Gijón ⁶ , Paul D Kennedy ⁶ , Jeffrey K Johnson ⁶ , Peng Liao ¹ ² , Xueting Lang ¹ ² ³ , Ilona Kryczek ¹ ² , Amanda Sell ¹ ² , Houjun Xia ¹ ² , Jiajia Zhou ¹ ² , Gaopeng Li ¹ ² , Jing Li ¹ ² , Wei Li ¹ ² , Shuang Wei ¹ ² , Linda Vatan ¹ ² , Hongjuan Zhang ¹ ² , Wojciech Szeliga ¹ ² , Wei Gu ⁷ , Rebecca Liu ⁸ , Theodore S Lawrence ³ , Candice Lamb ⁹ ¹⁰ , Yuri Tanno ⁹ ¹⁰ , Marcin Cieslik ⁴ ¹¹ , Everett Stone ⁹ ¹⁰ , George Georgiou ⁹ ¹⁰ , Timothy A Chan ¹² , Arul Chinnaiyan ⁴ ⁵ ¹³ , Weiping Zou ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
2. Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
3. Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
4. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
5. Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
6. Cayman Chemical Company, Ann Arbor, MI, USA.
7. Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
8. Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
9. Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.
10. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
11. Department of Computational Medicine & Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI, USA.
12. Immunogenomics and Precision Oncology Platform, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
13. Howard Hughes Medical Institute, University of Michigan School of Medicine, Ann Arbor, MI, USA.
14. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. [email protected].
15. Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. [email protected].
16. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA. [email protected].
17. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA. [email protected].
18. Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA. [email protected].

Abstract

Cancer Immunotherapy restores or enhances the effector function of CD8⁺ T cells in the tumour microenvironment^1,2. CD8⁺ T cells activated by Cancer Immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways^3,4. Ferroptosis is a form of cell death that differs from Apoptosis and results from iron-dependent accumulation of lipid peroxide^5,6. Although it has been investigated in vitro^7,8, there is emerging evidence that Ferroptosis might be implicated in a variety of pathological scenarios^9,10. It is unclear whether, and how, Ferroptosis is involved in T cell immunity and Cancer Immunotherapy. Here we show that immunotherapy-activated CD8⁺ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased Ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8⁺ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system x_c^-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and Ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced Ferroptosis in tumour cells. Expression of system x_c^- was negatively associated, in Cancer patients, with CD8⁺ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour Ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.