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NRF2-mediated immune evasion and ferroptosis resistance in hepatocellular carcinoma: implications for immune
Setya Jenio Malangi1, Dian Siswanto1, Mansur Ibrahim2
1Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, East Java, Indonesia.
Abstract:
Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality, and immune checkpoint inhibitors have become central to systemic treatment for advanced disease. However, durable responses are limited to a subset of patients, indicating the need to clarify tumor-intrinsic mechanisms that shape immune resistance. Nuclear factor erythroid 2-related factor 2 (NRF2), encoded by nuclear factor erythroid 2-related factor 2 like 2 (NFE2L2), is a stress-responsive transcription factor that regulates antioxidant defense, detoxification, metabolism, and redox adaptation. Although transient NRF2 activation protects hepatocytes from oxidative injury, persistent activation in HCC may promote tumor survival, immune escape, and resistance to therapy. Emerging evidence links NRF2 activity to two biologically connected processes: suppression of ferroptosis and remodeling of the tumor immune microenvironment. Through downstream targets involved in glutathione synthesis, cystine transport, iron handling, and lipid peroxide detoxification, NRF2 can reduce ferroptotic vulnerability. In parallel, NRF2-associated inflammatory and immune-regulatory pathways, including the cyclooxygenase-2-prostaglandin E2 axis, may contribute to immune-cold phenotypes and impaired response to immune checkpoint blockade. This review summarizes current evidence on NRF2/KEAP1 signaling in HCC, with emphasis on its role in immune escape, ferroptosis suppression, and its potential implications as a biomarker and therapeutic target for understanding and potentially improving immune checkpoint inhibitor responsiveness. We also discuss the potential of NRF2-related biomarkers and therapeutic strategies, while emphasizing the challenges of selectively targeting NRF2 in patients with underlying liver dysfunction.
Insights
Persistent activation of Nuclear factor erythroid 2-related factor 2 (NRF2) in liver cancer promotes immune escape and therapy resistance by suppressing ferroptosis. Targeting NRF2 may improve immune checkpoint inhibitor response in hepatocellular carcinoma.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, with immune checkpoint inhibitors (ICIs) offering limited durable responses in many patients.
- Tumor-intrinsic mechanisms driving immune resistance in HCC require elucidation to improve treatment efficacy.
- Nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor regulating cellular defense, is persistently activated in HCC, potentially promoting tumor survival and immune evasion.
Purpose of the Study:
- To review the current evidence on NRF2/KEAP1 signaling in HCC.
- To emphasize NRF2's role in immune escape and ferroptosis suppression.
- To explore NRF2 as a potential biomarker and therapeutic target for enhancing ICI responsiveness.
Main Methods:
- Literature review of studies on NRF2/KEAP1 signaling in hepatocellular carcinoma.
- Analysis of NRF2's downstream targets and pathways involved in ferroptosis and immune modulation.
- Synthesis of evidence linking NRF2 activity to immune-cold phenotypes and resistance to immunotherapy.
Main Results:
- Persistent NRF2 activation in HCC is linked to suppressed ferroptosis, reducing cancer cell vulnerability.
- NRF2 influences the tumor immune microenvironment, potentially creating immune-cold phenotypes via pathways like COX2-PGE2.
- These mechanisms contribute to impaired responses to immune checkpoint blockade in a subset of HCC patients.
Conclusions:
- NRF2 signaling plays a critical role in HCC immune escape and resistance to therapies like ICIs.
- NRF2-mediated suppression of ferroptosis and remodeling of the immune microenvironment are key mechanisms.
- NRF2 and related pathways represent potential biomarkers and therapeutic targets for improving HCC treatment outcomes, despite challenges in patients with liver dysfunction.
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