ArticleInternational journal of biological sciences2025
Overcoming Ferroptosis-Induced Exhaustion of NK Cells through Inhibition of the ATF3-Mediated Integrated Stress Response in Ovarian Cancer.
Article in International journal of biological sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Ferroptosis in T cells: mechanisms, biology and translational opportunities.Nature reviews. Immunology · 2026Review
- The ATF3-DRP1 Axis Coordinates Mitochondrial Homeostasis and Suppresses Early Apoptosis in Zinc-Deficient Cardiomyocytes.Biological trace element research · 2026Article
- The ATF3-DRP1 Axis Coordinates Mitochondrial Homeostasis and Suppresses Early Apoptosis in Zinc-Deficient Cardiomyocytes.Biological trace element research · 2026Article
- Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review).Oncology reports · 2026Review
Corrections and comments
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Authors and funding
10 authors.
Funding
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Abstract
The absence of cytotoxic effector cells, such as CD8⁺ T cells or Natural Killer (NK) cells, within tumors establishes an immune-cold tumor microenvironment (TME), contributing to poor immunotherapy responses, as observed in ovarian cancer. Although prior studies implicate NK cell exhaustion within the TME related to ferroptosis, the underlying mechanisms remain undefined. This study demonstrates that upon infiltrating the ovarian cancer TME, NK cells activate an integrated stress response (ISR) centered on ATF3. This ATF3-mediated ISR suppresses NRF2 expression, compromising their ability to counteract oxidative stress and ultimately triggering ferroptosis. Critically, we show that co-treatment with the ISR inhibitor ISRIB and NK cells not only prevents NK cell ferroptosis but also synergizes to enhance tumor cell killing. These findings provide novel insights into the mechanisms driving NK cell exhaustion within the TME and identify ISR inhibition as a promising therapeutic target and intervention strategy for developing NK cell-based therapies against ovarian cancer.
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