Journal of Liver Cancer

Review Article

NRF2-Mediated immune evasion and ferroptosis resistance in hepatocellular carcinoma: implications for immune checkpoint inhibitor response: Setya Jenio Malangi, Dian Siswanto, Mansur Ibrahim, Noviana Dwi Lestari, Muhaimin Rifa'i; Received May 27, 2026 Accepted June 28, 2026 Published online June 30, 2026; DOI: https://doi.org/10.17998/jlc.2026.06.28 [Accepted]

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Abstract PDF: 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 (COX2–PGE2) 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.

Original Article

Isolation and characterization of cancer-associated fibroblasts in the tumor microenvironment of hepatocellular carcinoma: Kyoungdo Mun, Jiwon Han, Pureun Roh, Jonggeun Park, Gahee Kim, Wonhee Hur, Jeongwon Jang, Jongyoung Choi, Seungkew Yoon, Youngkyoung You, Hojoong Choi, Pilsoo Sung; J Liver Cancer. 2023;23(2):341-349. Published online June 12, 2023; DOI: https://doi.org/10.17998/jlc.2023.04.30

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12 Citations

Abstract PDF

Background/Aim
Cancer-associated fibroblasts (CAFs) play an immunosuppressive role in the tumor microenvironment (TME) of human cancers; however, their characteristics and role in hepatocellular carcinoma (HCC) remain to be elucidated.
Methods
Nine tumor and surrounding liver tissue samples from patients with HCC who underwent surgery were used to isolate patient-derived CAFs. Cell morphology was observed using an optical microscope after culture, and cell phenotypes were evaluated using flow cytometry and immunoblotting. Cytokines secreted by CAFs into culture medium were quantified using a multiplex cytokine assay.
Results
CAFs were abundant in the TME of HCC and were adjacent to immune cells. After culture, the CAFs and non-tumor fibroblasts exhibited spindle shapes. We observed a robust expression of alpha-smooth muscle actin and fibroblast activation protein in CAFs, whereas alpha-fetoprotein, epithelial cell adhesion molecule, platelet/endothelial cell adhesion molecule-1, and E-cadherin were not expressed in CAFs. Furthermore, CAFs showed high secretion of various cytokines, namely C-X-C motif chemokine ligand 12, interleukin (IL)-6, IL-8, and C-C motif chemokine ligand 2.
Conclusions
CAFs are abundant in the TME of HCC and play a crucial role in tumor progression. These fibroblasts secrete cytokines that promote tumor growth and metastasis.

Citations

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Review Article

A clinical and pathological update on hepatocellular carcinoma: Salvatore Lorenzo Renne, Luca Di Tommaso; J Liver Cancer. 2022;22(1):14-22. Published online March 31, 2022; DOI: https://doi.org/10.17998/jlc.2022.03.18

23,238 Views
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24 Citations

Abstract PDF

It is estimated that more than 1 million individuals will be affected annually by hepatocellular carcinoma (HCC) by 2025. HCC can be broadly grouped into two major molecular subgroups, each of which is characterized by specific morphological and phenotypic features that mirror the genetic background. The use of these tissue biomarkers in the daily practice of pathologists promises to better allocate patients with HCC with adequate treatments. In turn, this will likely boost the attitude of clinicians toward obtaining a pre-treatment biopsy.

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