1. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer.
- Author
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Li, Jingbo, Liu, Jiao, Zhou, Zhuan, Wu, Runliu, Chen, Xin, Yu, Chunhua, Stockwell, Brent, Kroemer, Guido, Kang, Rui, and Tang, Daolin
- Subjects
PANCREATIC cancer ,LABORATORY mice ,IMMUNE response ,PANCREATIC tumors ,IMMUNE checkpoint proteins ,PANCREATIC intraepithelial neoplasia ,GLUTATHIONE peroxidase - Abstract
Lipid peroxidation–dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8
+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity. Editor's summary: Inducing ferroptotic cell death is an emerging treatment for cancer; however, because of its non-selective properties, it can also inhibit the immune cells. To overcome this, Li et al. have identified a small molecule compound, N6F11, that selectively triggered degradation of glutathione peroxidase 4 (GPX4), a ferroptosis repressor, in tumor cells and not immune cells. The authors further tested this in mouse models of pancreatic cancer, demonstrating that treatment increased sensitivity to immune checkpoint blockade (ICB). These preclinical results warrant further study of N6F11 and its potential benefit to improve efficacy of ICB in patients with cancer. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]- Published
- 2023
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