NRF2-mediated immune evasion and ferroptosis resistance in hepatocellular carcinoma: implications for immune checkpoint inhibitor response.

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.