Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment

  • Jialin Feng (Division of Cellular Medicine, School of Medicine, University of Dundee) ;
  • Oliver J. Read (Division of Cellular Medicine, School of Medicine, University of Dundee) ;
  • Albena T. Dinkova-Kostova (Division of Cellular Medicine, School of Medicine, University of Dundee)
  • Received : 2022.11.23
  • Accepted : 2022.12.12
  • Published : 2023.03.31
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Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of proinflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.

Keywords

Acknowledgement

We thank the Medical Research Council (MR/W023806/1) and the Ninewells Cancer Campaign for funding our research.

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