期刊
NATURE
卷 612, 期 7939, 页码 338-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-05443-0
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资金
- National Institute of Health [AI156924, CA243142, CA165065, 2T32DK007780-21, R01 CA266342, P30-CA016520, R01-CA-229803-01, P30DK046200, DK108722]
- University of Pennsylvania Biomedical Graduate Studies Program
- Wistar Institute Animal and Flow Cytometry Core facilities under Cancer Center Support Grant [P30 CA010815]
Ferroptosis is a unique and targetable immunosuppressive mechanism in the tumor microenvironment, which can be pharmacologically modulated to limit tumor progression. It induces spontaneous death of PMN-MDSCs in the tumor microenvironment and limits the activity of human and mouse T cells.
Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice1,2. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity3-5. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression.
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