Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance PMID: 42330950

ADC Targets in Oncology

2026-04-10

Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance

Cell. 2026 Jun 22:S0092-8674(26)00636-7. doi: 10.1016/j.cell.2026.05.036.

Guang Lei ¹ , Zhengze Lu ² , Zhihao Xu ² , Chen Braun ³ , David Huo ² , Jian Gao ⁴ , Lin Tan ⁵ , Ting Hong ² , Shengrong Wu ² , Mingchuang Sun ² , Xi Zhao ² , Qidong Li ² , Xiong Chen ² , Yuelong Yan ² , Hyemin Lee ² , Chao Mao ² , Li Zhuang ² , Li-Ting Ku ⁶ , Nahum Puebla ³ , Hampartsoum Barsoumian ³ , Jun Yao ⁴ , Lingzhi Hong ⁷ , Jianjun Zhang ⁷ , Hai Tran ⁷ , Jiun-Kae Jack Lee ⁶ , Don Gibbons ⁷ , Ara Vaporciyan ⁸ , John Heymach ⁷ , Chunru Lin ⁴ , Eyal Gottlieb ⁹ , Mingjian James You ¹⁰ , James W Welsh ³ , Steven H Lin ³ , Xingxing Zang ¹¹ , Ziyi Li ⁶ , Boyi Gan ¹²

Affiliations

1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4. Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5. Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6. Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7. Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8. Department of Thoracic and Cardiovascular Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10. Department 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.
11. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
12. Department 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.

Keywords

CD8(+) T cell; FDX1; cuproptosis; immunogenic cell death; immunotherapy resistance.