Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance - Research Paper

Sep 24, 2026

Uploaded by Mimi

In human cancer, activating mutations in the KEAP1-NRF2 pathway are frequently selected because NRF2 protects cancer cells, promoting aggressive, therapy-resistant tumors. Clinical advances also show that NRF2-activated cancers resist immune checkpoint inhibitor drugs. Since NRF2’s classic cytoprotective mechanism is tangential to immune modulation, how NRF2 alters immune anti-cancer function remains unclear. The study finds NRF2-activated cells undergo immunoediting, reducing MHC-I antigen presentation and NK activating ligands, limiting immune infiltration and creating an immunologically cold microenvironment.

LanguageEnglish

CategoryHealthcare

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Pages14

Reading Time35 min

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Introduction

KEAP1-NRF2 pathway and NRF2 regulation

NRF2 roles in cancer progression

Immunoediting and immune evasion

Redox Biology 67 (2023) 102904 Contents lists available at ScienceDirect Redox Biology journal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox) | Research Paper
Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance
Liam Baird a, b, **, Masayuki Yamamoto a, b, *
a Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan b Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai 980-8575, Japan | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
KEAP1
NRF2
NFE2L2
Stress response Oxidative stress NISP
Immune surveillance Immunoediting
Immune evasion | | In human cancer, activating mutations in the KEAP1-NRF2 pathway are frequently observed, and positively selected for, as they confer the cytoprotective functions of the transcription factor NRF2 on the cancer cells. This results in the development of aggressive tumours which are resistant to treatment with chemotherapeutic compounds. Recent clinical developments have also revealed that NRF2-activated cancers are similarly resistant to immune checkpoint inhibitor drugs. As the mechanism of action of these immune modulating therapies is tangential to the classical cytoprotective function of NRF2, it is unclear how aberrant NRF2 activity could impact the anti-cancer functionality of the immune system. In this context, we found that in human cancer, NRF2-activated cells are highly immunoedited, which allows the cancer cells to escape immune surveillance and develop into malignant tumours. This immunoediting takes the form of reduced antigen presentation by the MHC-I complex, coupled with reduced expression of activating ligands for NK cells. Together, these modifications to the immunogenicity of NRF2-activated cancers inhibit immune effector cell infiltration and engagement, and contribute to the formation of the immunologically cold tumour microenvironment which is a characteristic feature of NRF2-activated cancers. | 1. Introduction The KEAP1-NRF2 pathway functions as a critical signaling node which protects cells from a broad range of electrophilic and oxidative stresses [1,2]. NRF2 is a transcription factor which regulates the expression of a myriad of cytoprotective genes, the protein products of which function in concert to allow cells to repair, adapt and survive in response to damage caused by both endogenous and environmental stressors [3,4]. The activity of NRF2 is tightly regulated by KEAP1, which is an adaptor protein for a Cullin 3-dependent E3 ubiquitin ligase [5]. Under non-stressed conditions, KEAP1 targets NRF2 for ubiquitination and proteasome-dependent degradation, which, under homeostatic conditions, maintains NRF2-target gene expression at low levels [6,7]. In response to stress, electrophiles and reactive oxygen species (ROS) bind to a number of highly reactive cysteine-based sensors within the KEAP1 protein [8,9]. This direct sensing of stressor molecules results in a conformation change in the KEAP1 protein such that it is no longer able to target NRF2 for ubiquitination and proteasome-dependent degradation [10]. As a result, NRF2 accumulates within the cell and translocates to the nucleus, where it induces cytoprotective gene expression to promote cellular survival in response to the original pathway-inducing cytotoxic stressor [11,12]. Consistent with the cytoprotective functions of NRF2, its genetic deletion in mice results in increased tumourigenesis in response to a range of chemical carcinogens [13,14]. Despite the fact that NRF2 has a well-described and experimentally supported tumour suppressor function in non-transformed cells, genetic activation of NRF2 is frequently observed in human cancer patients, which

FAQs

What is the KEAP1-NRF2 pathway’s primary role in cells?

It acts as a signaling node that protects cells from electrophilic and oxidative stresses by regulating cytoprotective gene expression.

Why are KEAP1-NRF2 activated tumors often resistant to treatment?

Activating mutations confer NRF2-dependent cytoprotective advantages and are associated with resistance to immune checkpoint inhibitor drugs.

How does NRF2 activation enable immune evasion in the described study?

NRF2-activated cells show immunoediting characterized by reduced MHC-I antigen presentation and reduced expression of NK activating ligands, which weakens immune cell infiltration and engagement.

Sep 24, 2026

Uploaded by Mimi