TY - JOUR
T1 - NRF2 immunobiology in cancer
T2 - implications for immunotherapy and therapeutic targeting
AU - Panda, Harit
AU - Rowland, Natalie G.
AU - Krall, Caroline M.
AU - Bowman, Brittany M.
AU - Major, Michael B.
AU - Zolkind, Paul
N1 - Publisher Copyright:
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.
PY - 2025/10/14
Y1 - 2025/10/14
N2 - Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that acts as a key regulator in cellular defense mechanisms against oxidative stress and xenobiotics. NRF2 modulates the expression of over 200 genes involved in antioxidant response, drug metabolism, and cellular resilience. Constitutive activation of NRF2 is a common event in cancer and recent advances provide remarkable insights into the role of NRF2 in oncogenesis, immune evasion, and treatment resistance. This review aims to provide a comprehensive overview of the role of NRF2 in shaping the tumor immune microenvironment and the impact this has on clinical outcomes and treatment opportunities. Across multiple tumor subtypes, the activation of NRF2 is associated with impaired responses to anti-PD1 immunotherapy. Mechanistic insights from genetically engineered mouse models, in vitro studies, and clinical trial samples demonstrate how NRF2 activity supports cell resiliency, diminishes cytotoxic immune responses, and promotes metabolic reprogramming. This also provides a vulnerability which can be targeted through novel drug therapy and future directions will include development of optimal combination strategies to target tumor dependencies while minimizing toxicity and systemic off-target immune related effects.
AB - Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that acts as a key regulator in cellular defense mechanisms against oxidative stress and xenobiotics. NRF2 modulates the expression of over 200 genes involved in antioxidant response, drug metabolism, and cellular resilience. Constitutive activation of NRF2 is a common event in cancer and recent advances provide remarkable insights into the role of NRF2 in oncogenesis, immune evasion, and treatment resistance. This review aims to provide a comprehensive overview of the role of NRF2 in shaping the tumor immune microenvironment and the impact this has on clinical outcomes and treatment opportunities. Across multiple tumor subtypes, the activation of NRF2 is associated with impaired responses to anti-PD1 immunotherapy. Mechanistic insights from genetically engineered mouse models, in vitro studies, and clinical trial samples demonstrate how NRF2 activity supports cell resiliency, diminishes cytotoxic immune responses, and promotes metabolic reprogramming. This also provides a vulnerability which can be targeted through novel drug therapy and future directions will include development of optimal combination strategies to target tumor dependencies while minimizing toxicity and systemic off-target immune related effects.
UR - https://www.scopus.com/pages/publications/105016267684
U2 - 10.1038/s41388-025-03560-4
DO - 10.1038/s41388-025-03560-4
M3 - Review article
C2 - 40946102
AN - SCOPUS:105016267684
SN - 0950-9232
VL - 44
SP - 3641
EP - 3651
JO - Oncogene
JF - Oncogene
IS - 39
ER -