Peer-reviewedCC BYCell
Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance
12 affiliations
- 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected]
- 2Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 3Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 4Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 5Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 6Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 7Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 8Department of Thoracic and Cardiovascular Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 9Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 10Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- 11Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- 12Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: [email protected]
Abstract
Cuproptosis is a recently identified form of copper-dependent cell death that depends on ferredoxin 1 (FDX1)-mediated protein lipoylation. Here, we reveal that CD8 + T cell-mediated antitumor immunity enhances tumor cell susceptibility to cuproptosis, leading to a more potent tumor-suppressive effect of cuproptosis inducers in immunocompetent hosts compared with immunodeficient ones. Mechanistically, cuproptotic tumor cells act as a form of immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and enhance antitumor immunity. Reciprocally, CD8 + T cell-derived interferon (IFN)-γ enhances FDX1 transcription in tumor cells by activating the signal transducer and activator of transcription 1 (STAT1)-IFN regulatory factor-1 (IRF1) signaling axis, resulting in heightened tumor cell sensitivity to cuproptosis. Consequently, combining a cuproptosis inducer with anti-programmed cell death ligand 1 (PD-L1) therapy amplifies tumoral cuproptosis and demonstrates efficacy in overcoming PD-L1 therapy resistance across multiple preclinical models. Our findings unveil a previously unrecognized connection between antitumor immunity and cuproptosis and highlight a potential therapeutic approach to counteract tumor immunotherapy resistance by targeting this unique cell death pathway.
Related
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- Post-Translational Control of PD-L1 in Cancer Immunity and Immunotherapy Resistance
BibTeX
@article{lei2026cuproptosisimmunity,
title = {{Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance}},
author = {Guang Lei and Zhengze Lu and Zhihao Xu and Chen Braun and David Huo and Jian Gao and Lin Tan and Ting Hong and Shengrong Wu and Mingchuang Sun and Xi Zhao and Qidong Li and Xiong Chen and Yuelong Yan and Hyemin Lee and Chao Mao and Z G Li and Li-Ting Ku and Nahum Puebla‐Osorio and Hampartsoum B. Barsoumian and Jun Yao and Lingzhi Hong and Jianjun Zhang and Hai T. Tran and Jiun-Kae Jack Lee and Don Gibbons and Ara J. Vaporciyan and John Victor Heymach and Chunru Lin and Eyal Gottlieb and You Mj and James W. Welsh and Steven H. Lin and Xingxing Zang and Z G Li and Boyi Gan},
journal = {Cell},
year = {2026},
month = jun,
doi = {10.1016/j.cell.2026.05.036},
url = {https://doi.org/10.1016/j.cell.2026.05.036},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance
AU - Guang Lei
AU - Zhengze Lu
AU - Zhihao Xu
AU - Chen Braun
AU - David Huo
AU - Jian Gao
AU - Lin Tan
AU - Ting Hong
AU - Shengrong Wu
AU - Mingchuang Sun
AU - Xi Zhao
AU - Qidong Li
AU - Xiong Chen
AU - Yuelong Yan
AU - Hyemin Lee
AU - Chao Mao
AU - Z G Li
AU - Li-Ting Ku
AU - Nahum Puebla‐Osorio
AU - Hampartsoum B. Barsoumian
AU - Jun Yao
AU - Lingzhi Hong
AU - Jianjun Zhang
AU - Hai T. Tran
AU - Jiun-Kae Jack Lee
AU - Don Gibbons
AU - Ara J. Vaporciyan
AU - John Victor Heymach
AU - Chunru Lin
AU - Eyal Gottlieb
AU - You Mj
AU - James W. Welsh
AU - Steven H. Lin
AU - Xingxing Zang
AU - Z G Li
AU - Boyi Gan
PY - 2026
DA - 2026/06/22
JO - Cell
DO - 10.1016/j.cell.2026.05.036
UR - https://doi.org/10.1016/j.cell.2026.05.036
AB - Cuproptosis is a recently identified form of copper-dependent cell death that depends on ferredoxin 1 (FDX1)-mediated protein lipoylation. Here, we reveal that CD8 + T cell-mediated antitumor immunity enhances tumor cell susceptibility to cuproptosis, leading to a more potent tumor-suppressive effect of cuproptosis inducers in immunocompetent hosts compared with immunodeficient ones. Mechanistically, cuproptotic tumor cells act as a form of immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and enhance antitumor immunity. Reciprocally, CD8 + T cell-derived interferon (IFN)-γ enhances FDX1 transcription in tumor cells by activating the signal transducer and activator of transcription 1 (STAT1)-IFN regulatory factor-1 (IRF1) signaling axis, resulting in heightened tumor cell sensitivity to cuproptosis. Consequently, combining a cuproptosis inducer with anti-programmed cell death ligand 1 (PD-L1) therapy amplifies tumoral cuproptosis and demonstrates efficacy in overcoming PD-L1 therapy resistance across multiple preclinical models. Our findings unveil a previously unrecognized connection between antitumor immunity and cuproptosis and highlight a potential therapeutic approach to counteract tumor immunotherapy resistance by targeting this unique cell death pathway.
SN - 0092-8674
SN - 1097-4172
ER -