Nrf2 in TIME: The emerging role of nuclear factor erythroid 2-related factor 2 in the tumor immune microenvironment

TY - JOUR

T1 - Nrf2 in TIME

T2 - The emerging role of nuclear factor erythroid 2-related factor 2 in the tumor immune microenvironment

AU - Feng, Jialin

AU - Read, Oliver J.

AU - Dinkova-Kostova, Albena T.

N1 - Funding Information: We thank the Medical Research Council (MR/W023806/1) and the Ninewells Cancer Campaign for funding our research. Copyright: © The Korean Society for Molecular and Cellular Biology.

PY - 2023/3/31

Y1 - 2023/3/31

N2 - 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 pro-inflammatory 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.

AB - 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 pro-inflammatory 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.

KW - anti-tumor immunity

KW - immunosuppression

KW - Keap1

KW - Nrf2

KW - tumor microenvironment

UR - https://www.scopus.com/pages/publications/85151312430

U2 - 10.14348/molcells.2023.2183

DO - 10.14348/molcells.2023.2183

M3 - Review article

C2 - 36927604

SN - 0219-1032

VL - 46

SP - 142

EP - 152

JO - Molecules and Cells

JF - Molecules and Cells

IS - 3

ER -