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.

INTRODUCTION

Hepatocellular carcinoma (HCC) remains a major clinical challenge because it usually arises in chronically injured liver tissue, including cirrhosis, viral hepatitis, metabolic dysfunction, and persistent inflammation. Immune checkpoint inhibitors (ICIs), particularly agents targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, have reshaped the treatment landscape of advanced HCC. Nevertheless, only a proportion of patients achieve durable benefit, suggesting that ICI resistance is driven by complex interactions among tumor-intrinsic signaling, immune-cell composition, antigen presentation, metabolic adaptation, angiogenesis, and liver-specific immune tolerance.¹

Nuclear factor erythroid 2-related factor 2 (NRF2), encoded by nuclear factor erythroid 2-related factor 2 like 2 (NFE2L2), is a master regulator of cellular stress adaptation. Under basal conditions, NRF2 is restrained by Kelch-like ECH-associated protein 1 (KEAP1)-mediated ubiquitination and proteasomal degradation. In response to oxidative or electrophilic stress, or through genetic and non-genetic alterations affecting the NRF2-KEAP1 axis, NRF2 accumulates in the nucleus and activates antioxidant response element-driven genes involved in redox control, detoxification, glutathione metabolism, cystine transport, and cytoprotection.^2,3

During liver carcinogenesis, NRF2 activity may have divergent effects. Transient NRF2 activation helps protect hepatocytes from oxidative injury and inflammation, whereas sustained activation in malignant cells can support tumor survival, metabolic adaptation, drug tolerance, and immune escape. This shift from cytoprotection to tumor promotion is important in HCC, where cancer cells develop under persistent inflammatory and oxidative pressure.⁴

A key mechanism connecting NRF2 activation with treatment resistance is ferroptosis suppression. Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and failure of antioxidant defense. Because NRF2 controls genes involved in glutathione synthesis, cystine uptake, iron metabolism, and lipid peroxide detoxification, sustained NRF2 signaling can reduce ferroptotic vulnerability in cancer cells. In HCC, ferroptosis-related pathways are increasingly recognized as relevant to resistance against targeted therapy and may also influence antitumor immunity.^5,6

NRF2 may also affect ICI response by shaping the tumor immune microenvironment. High NRF2 activity can reduce oxidative stress-mediated tumor cell killing, limit ferroptosis-associated immunogenic signals, and promote immune-cold or immunosuppressive features. Emerging HCC-specific evidence suggests that NRF2-associated pathways, including the NRF2-cyclooxygenase-2 (COX2)-prostaglandin E2 (PGE2) axis, may contribute to poor response to ICI-based therapy, while experimental NRF2 inhibition may enhance antitumor immunity and immunotherapy sensitivity.^7,8

Although previous reviews have discussed the role of NRF2 signaling in HCC and the broader immunobiology of NRF2 in cancer, the present review specifically focuses on the integrated relationship among NRF2 activation, ferroptosis resistance, immune evasion, and ICI responsiveness in HCC. By synthesizing these interconnected processes within a single conceptual framework, this review aims to highlight potential mechanistic links, translational implications, and biomarker opportunities that have not been comprehensively addressed in prior publications.

Therefore, NRF2 may represent a biologically plausible link between ferroptosis resistance, immune evasion, and ICI resistance in HCC. This review summarizes current evidence on NRF2/KEAP1 signaling in HCC, with emphasis on its role in immune escape, ferroptosis suppression, and potential implications as a biomarker or therapeutic target for improving ICI response.

REVIEW METHODOLOGY

This narrative review was conducted to provide an overview of current evidence regarding NRF2/KEAP1 signaling, ferroptosis resistance, immune evasion, and ICI responsiveness in HCC. Relevant literature was identified primarily through searches of the PubMed/MEDLINE database using combinations of terms including “hepatocellular carcinoma,” “NRF2,” “NFE2L2,” “KEAP1,” “immune evasion,” “tumor immune microenvironment,” “ferroptosis,” “solute carrier family 7 member 11 (SLC7A11),” “glutathione peroxidase 4 (GPX4),” “ICI,” “PD-1,” “PD-L1,” and “immunotherapy.” Additional relevant articles were identified from the reference lists of selected publications. The literature was selected based on relevance to the scope of this narrative review and was not intended to represent a systematic or exhaustive assessment of all available studies.

NRF2/KEAP1 SIGNALING IN HEPATOCARCINOGENESIS

NRF2 is a central transcription factor that maintains cellular redox homeostasis by regulating antioxidant, detoxification, metabolic, and cytoprotective genes. Under basal conditions, NRF2 is bound by KEAP1, which promotes NRF2 ubiquitination and proteasomal degradation. During oxidative or electrophilic stress, NRF2 escapes KEAP1-mediated degradation, translocates into the nucleus, and activates antioxidant response element-driven genes, including NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), and SLC7A11.²

In the liver, NRF2 signaling has a context-dependent role. Physiological NRF2 activation protects hepatocytes from oxidative injury and inflammation; however, sustained NRF2 activation may support hepatocarcinogenesis by promoting tumor cell survival, metabolic adaptation, and resistance to anticancer therapy. This dual function is particularly relevant in HCC, which frequently arises in chronically inflamed and oxidatively stressed liver tissue.⁴

Although activating NFE2L2 mutations and inactivating KEAP1 alterations represent established mechanisms of NRF2 pathway activation, these genomic events occur in only a minority of HCC cases. Data from The Cancer Genome Atlas (TCGA) and other genomic studies indicate that NRF2 pathway dysregulation in HCC frequently involves non-mutational mechanisms, including sequestosome 1 (p62/SQSTM1) accumulation, impaired autophagic degradation, and oxidative stress-mediated NRF2 stabilization. This distinction is clinically important because biomarker development and therapeutic strategies may need to account for both genetic and non-genetic modes of NRF2 activation.^4,8

Aberrant NRF2 activation in HCC can occur through several mechanisms, including NFE2L2 or KEAP1 alterations, impaired autophagic degradation, and accumulation of p62/SQSTM1. p62 can competitively bind KEAP1, thereby preventing KEAP1-mediated NRF2 degradation and leading to persistent NRF2 transcriptional activity. This p62-KEAP1-NRF2 axis has been implicated in liver tumorigenesis, tumor growth, and treatment resistance.⁹

Importantly, NRF2 activation is also linked to ferroptosis resistance in HCC. Sun et al.⁹ demonstrated that activation of the p62-KEAP1-NRF2 pathway protects HCC cells from ferroptosis by regulating antioxidant and iron metabolism-related genes. This finding provides a mechanistic basis for connecting NRF2 activity with therapy resistance in HCC, including resistance to treatments that depend on oxidative stress or lipid peroxidation-mediated tumor cell death.^9,10 The key original and translational studies supporting the role of NRF2/KEAP1 signaling in ferroptosis resistance, immune evasion, and ICI response in HCC are summarized in Table 1.

Table 1.

NRF2/KEAP1 pathway in ferroptosis, immune evasion, and ICI response

Study	Evidence level/model	Sample/model detail	NRF2/KEAP1-related mechanism	Main finding	Relevance
Sun et al.9 (2016)	In vitro HCC study	HCC cell lines treated with ferroptosis inducers	p62-KEAP1-NRF2 axis	p62-KEAP1-NRF2 activation protected HCC cells from ferroptosis	Direct evidence for NRF2-mediated ferroptosis resistance in HCC
Tang et al.14 (2022)	In vitro and in vivo HCC study	HCC cells and xenograft models treated with metformin plus sorafenib	p62-KEAP1-NRF2/HO-1 pathway	Combination treatment induced ferroptosis by inhibiting NRF2-related signaling and reduced xenograft growth	Supports therapeutic targeting of NRF2-associated ferroptosis resistance
Yamamoto et al.12 (2026)	Patient cohort and translational HCC study	HCC patients receiving atezolizumab/bevacizumab plus experimental models	NRF2-COX2-PGE2 axis	Tumor-intrinsic NRF2-COX2-PGE2 activation was associated with an immune-cold TME and reduced responsiveness to atezolizumab/bevacizumab	Represents the strongest currently available clinical associations between NRF2 activation and reduced responsiveness to ICIbased therapy in HCC
Zhu et al.7 (2026)	Recent in vitro, in vivo, and translational HCC study	HCC cell models, animal models, and immune-related analyses	Targeted NRF2 inhibition	NRF2 inhibition potentiated antitumor immunity and enhanced immunotherapy efficacy in HCC	Provides preclinical and translational evidence supporting NRF2 targeting as a potential strategy to enhance immunotherapy response in HCC

NRF2, nuclear factor erythroid 2-related factor 2; KEAP1, Kelch-like ECH-associated protein 1; ICI, immune checkpoint inhibitor; HCC, hepatocellular carcinoma; p62/SQSTM1, sequestosome 1; HO-1, heme oxygenase 1; COX2, cyclooxygenase-2; PGE2, prostaglandin E2; TME, tumor microenvironment.

NRF2-DRIVEN IMMUNE EVASION IN HEPATOCELLULAR CARCINOMA

Beyond its canonical role in redox regulation, NRF2 signaling has been increasingly implicated in mechanisms of tumor immune escape. NRF2 activation can alter oxidative stress, inflammatory signaling, cytokine production, and tumor-immune cell interactions, thereby shaping the tumor immune microenvironment and potentially influencing the response to immunotherapy. ¹¹ Evidence linking NRF2 signaling to immune evasion in HCC currently derives from a combination of HCC-specific studies and mechanistic observations from other tumor types. Where applicable, distinctions between direct HCC evidence and broader cancer biology findings are highlighted below.

In HCC, this concept is particularly relevant because the liver is an immunologically unique organ, and HCC commonly develops in a background of chronic inflammation, fibrosis, and immune tolerance. The HCC tumor microenvironment contains multiple immunosuppressive components, including regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, exhausted T cells, and altered cytokine networks, all of which can reduce effective antitumor immunity.¹²

One clinically relevant mechanism involves the formation of an immune-cold tumor microenvironment. Yamamoto et al.¹² reported that tumor-intrinsic activation of the NRF2-COX2-PGE2 axis was associated with immune-cold tumors and resistance to atezolizumab plus bevacizumab in HCC. This finding suggests that NRF2 activation may promote immune evasion not only through intracellular antioxidant defense but also through inflammatory lipid mediator signaling that limits cytotoxic immune infiltration and function.

NRF2 activation may also impair innate immune sensing. Li et al.¹³ reported that NRF2 gain-of-function mutation reduced stimulator of interferon genes (STING) expression and decreased immune cell infiltration, thereby promoting tumor immune escape. Importantly, these findings were not derived exclusively from HCC models and should therefore be considered mechanistic evidence that may not fully reflect HCC-specific biology. Further studies are required to determine whether NRF2-mediated STING suppression contributes to immune evasion in HCC patients. Although this study was not limited to HCC, it provides a mechanistic rationale by which tumor-intrinsic NRF2 activation may suppress antitumor immune surveillance. Therefore, the relevance of NRF2-mediated STING suppression in HCC should currently be regarded as mechanistically plausible rather than definitively established.

This evidence has clinical relevance because ICIs require pre-existing or inducible antitumor immune activity. When NRF2 activation favors an immune-cold or immunosuppressive tumor milieu, tumors with high NRF2 activity could be associated with reduced responsiveness to PD-1/PD-L1-based therapy. In line with this mechanism, targeted NRF2 inhibition has been shown to strengthen antitumor immunity and improve immunotherapy efficacy in HCC models.⁸ Overall, the available evidence supports NRF2 as a candidate biomarker and therapeutic target for overcoming immune evasion in HCC.

NRF2-ASSOCIATED FERROPTOSIS RESISTANCE IN HEPATOCELLULAR CARCINOMA

Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and failure of antioxidant defense systems. Unlike apoptosis, ferroptosis is closely linked to cellular redox balance, glutathione metabolism, iron handling, and lipid peroxide detoxification. These processes are highly relevant to HCC because liver cancer cells frequently adapt to oxidative stress and metabolic pressure during tumor progression and treatment exposure.⁵

NRF2 is a key regulator of ferroptosis resistance because it controls multiple genes involved in antioxidant defense, glutathione synthesis, cystine transport, iron metabolism, and lipid peroxide detoxification. NRF2 downstream targets such as SLC7A11, GCLC, GCLM, NQO1, HMOX1, and GPX4-related antioxidant systems can reduce lipid peroxidation and protect tumor cells from ferroptotic death.^2,5

Experimental work in liver cancer models supports this mechanism. Sun et al.⁹ showed that activation of the p62-KEAP1-NRF2 pathway protects HCC cells from ferroptosis by regulating antioxidant and iron metabolism-related genes. Tang et al.¹⁴ further reported that metformin combined with sorafenib induced ferroptosis through modulation of the p62-KEAP1-NRF2/HO-1 pathway. These studies indicate that NRF2 activity may help tumor cells withstand treatments that depend on oxidative stress and ferroptotic cell death.

Ferroptosis resistance may also influence antitumor immunity. Ferroptotic tumor cell death can release immunogenic signals and reshape immune responses within the tumor microenvironment. Therefore, suppression of ferroptosis by NRF2 activation may reduce tumor immunogenicity and contribute to immune escape. However, much of the evidence supporting the ferroptosis-immunity connection originates from experimental studies and broader cancer models rather than direct HCC-specific investigations. This provides a mechanistic bridge between NRF2-mediated redox adaptation and impaired response to immune checkpoint blockade.

From a therapeutic perspective, targeting NRF2-associated ferroptosis resistance may increase the vulnerability of HCC cells to immune-mediated killing. Strategies that combine ferroptosis induction with ICIs are biologically plausible, but their clinical application requires caution because NRF2 also protects normal hepatocytes from oxidative injury. Therefore, future studies should define patient subsets, biomarkers, and dosing strategies that can selectively target NRF2-dependent tumor adaptation while preserving liver function. Based on these mechanisms, NRF2 activation may be positioned as a central link between ferroptosis resistance and immune evasion in HCC. The proposed integrated model is illustrated in Fig. 1.

Figure 1.

Proposed integrated model of NRF2-mediated immune evasion and ferroptosis resistance in HCC. HCC, hepatocellular carcinoma; NRF2, nuclear factor erythroid 2-related factor 2; COX2, cyclooxygenase-2; PGE2, prostaglandin E2; KEAP1, Kelch-like ECH-associated protein 1; NFE2L2, nuclear factor erythroid 2-related factor 2 like 2; p62/SQSTM1, sequestosome 1; NQO1, NAD(P)H quinone dehydrogenase 1; HO-1, heme oxygenase 1; SLC7A11, solute carrier family 7 member 11; GPX4, glutathione peroxidase 4; GCLC, glutamate-cysteine ligase catalytic subunit; TME, tumor microenvironment; Treg, regulatory T cells; MDSC, myeloid-derived suppressor cell; GSH, glutathione.

Proposed hypothesis-based model integrating HCC-specific and broader mechanistic evidence linking NRF2 activation, ferroptosis resistance, immune evasion, and ICI responsiveness in HCC. Persistent NRF2 activation through KEAP1 inactivation, NFE2L2 alteration, or p62/SQSTM1 accumulation promotes transcriptional programs involved in antioxidant defense and ferroptosis resistance. Current evidence suggests that NRF2 signaling may also contribute to immune-cold or immunosuppressive tumor phenotypes through mechanisms including the COX2/PGE2 axis and altered antitumor immune activity. The level of evidence supporting each mechanism is indicated within the figure, with HCC-specific findings distinguished from broader mechanistic observations derived from other cancer models.^8-10,12-14 This figure is an original work created by the authors.

IMPACT ON IMMUNE CHECKPOINT INHIBITOR RESPONSE

ICIs are now central to systemic therapy for advanced HCC. In the phase 3 IMbrave150 trial, atezolizumab plus bevacizumab improved overall and progression-free survival compared with sorafenib in unresectable HCC.¹⁵ The HIMALAYA trial also showed an overall survival benefit with tremelimumab plus durvalumab compared with sorafenib, supporting dual checkpoint blockade as another first-line option.¹⁶ Earlier studies of nivolumab and pembrolizumab reported durable responses in a subset of patients, although overall response remained variable. ^17,18 However, subsequent phase III trials of ICI monotherapy, including CheckMate 459 and KEYNOTE-240, did not meet their predefined primary endpoints despite demonstrating clinical benefit in selected patient subgroups.^19,20 These findings contributed to the transition toward combination-based immunotherapy strategies and further underscore the need for predictive biomarkers capable of identifying patients most likely to benefit from immune checkpoint blockade. This variability suggests that ICI efficacy is influenced not only by checkpoint blockade itself, but also by tumor-intrinsic signaling and the immune composition of the tumor microenvironment.²¹

NRF2 activation may reduce ICI responsiveness through two interconnected mechanisms. First, NRF2-driven antioxidant and cytoprotective programs can protect HCC cells from oxidative stress and ferroptosis, thereby limiting tumor cell death and reducing the release of immunogenic signals.^5,9,14 Second, NRF2 activation may promote an immune-cold or immunosuppressive microenvironment, as shown by the NRF2-COX2-PGE2 axis associated with resistance to atezolizumab plus bevacizumab in HCC.¹² Because effective ICI response requires pre-existing or inducible antitumor immunity, NRF2-high tumors may be less responsive to PD-1/PD-L1-based therapy if they are both resistant to ferroptotic cell death and less permissive to cytotoxic immune infiltration.

Clinical biomarker studies further support the importance of antitumor immune activity in determining ICI response. Integrated molecular analyses of patients treated with atezolizumab plus bevacizumab showed that high CD274 expression, T-effector signatures, and intratumoral CD8+ T cell density were associated with better clinical outcomes, whereas immune-suppressive and angiogenic features were linked to resistance.²² Broader biomarker reviews also emphasize that no single marker, including PD-L1 expression, tumor mutational burden, or immune-cell infiltration, is sufficient to predict ICI response in HCC across clinical settings.²³ Therefore, NRF2 should be investigated as part of integrated biomarker panels that combine tumor-intrinsic signaling, ferroptosis-related markers, angiogenic features, and immune profiling.

The biological link between ferroptosis and immunotherapy provides an additional rationale for studying NRF2 in ICI resistance. CD8+ T cells can promote ferroptosis in tumor cells through interferon-γ-mediated suppression of system X_c⁻ activity (the cystine/glutamate antiporter), thereby connecting cytotoxic immunity with lipid peroxidation-dependent tumor cell death.²⁴ If NRF2 activation enhances antioxidant defense and ferroptosis resistance, it may counteract this immune-mediated vulnerability. This mechanism may be particularly relevant in HCC, where oxidative stress adaptation, metabolic rewiring, and immune tolerance coexist within the tumor microenvironment.

Supporting this concept, targeted inhibition of NRF2 has been reported to enhance antitumor immunity and improve immunotherapy efficacy in HCC models.⁸ However, ICI resistance in HCC is multifactorial and also involves impaired antigen presentation, exhausted T cells, regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, angiogenesis, gut microbiota, and liver-specific immune tolerance.^25,26 Thus, NRF2-mediated immune evasion should be viewed as one component of a broader resistance network rather than a standalone determinant of ICI failure.

THERAPEUTIC IMPLICATIONS AND CLINICAL CHALLENGES

The integration of NRF2-mediated immune evasion and ferroptosis resistance provides several therapeutic implications for HCC. First, NRF2 inhibition may increase tumor vulnerability to oxidative stress, ferroptosis, and immune-mediated killing. Experimental evidence suggests that targeting NRF2 can potentiate antitumor immunity and enhance the efficacy of immunotherapy in HCC models.⁸ However, this strategy requires careful evaluation because NRF2 also protects normal hepatocytes from oxidative injury, and pharmacological NRF2 inhibition remains limited by issues of selectivity, off-target effects, toxicity, and clinical translation.²⁷

Second, combining ferroptosis induction with immune checkpoint blockade may represent a rational therapeutic approach. Since NRF2 activation can suppress lipid peroxidation and ferroptotic cell death, pharmacologic strategies that inhibit NRF2-associated antioxidant pathways or enhance ferroptosis may improve tumor immunogenicity and sensitize HCC to ICI-based therapy.^5,10,11,28 Ferroptosis-targeted strategies are increasingly being explored in HCC, including modulation of system X_c⁻, GPX4, glutathione metabolism, iron metabolism, and lipid peroxidation pathways.^29,30 Nevertheless, the optimal timing, dose, and patient selection for combining ferroptosis induction with immunotherapy remain unclear.

Third, the NRF2-COX2-PGE2 axis may offer a clinically relevant target for reversing immune-cold tumors. In HCC, activation of this pathway has been associated with resistance to atezolizumab plus bevacizumab, suggesting that inflammatory lipid mediator signaling may contribute to poor ICI response.¹² Targeting COX2/PGE2-related immunosuppression may help restore antitumor immune activity, although prospective validation in HCC is still needed.³¹

Several clinical challenges must be addressed before NRF2-directed strategies can be translated into routine practice. These include the lack of selective and clinically approved NRF2 inhibitors, potential hepatotoxicity, heterogeneity of NRF2 activation mechanisms, and absence of standardized biomarkers to identify NRF2-high tumors.^27,32 This is particularly important in HCC, where underlying cirrhosis, chronic viral hepatitis, metabolic liver disease, and impaired liver reserve can limit the safety of combination therapy.^31,32

An additional challenge is that NRF2 serves important hepatoprotective functions in non-malignant liver tissue. Because many patients with HCC have underlying cirrhosis, portal hypertension, chronic viral hepatitis, or metabolic dysfunction-associated liver disease, systemic NRF2 inhibition may increase susceptibility to oxidative injury and hepatic decompensation. Likewise, excessive induction of ferroptosis could potentially damage non-tumorous hepatocytes and worsen underlying liver dysfunction. These considerations highlight the need for tumor-selective therapeutic strategies, careful patient selection, and close monitoring of liver function in future clinical studies evaluating NRF2-targeted or ferroptosis-based approaches.^27,29,33

Beyond its role in hepatocytes, NRF2 signaling is also active in multiple immune-cell populations. Experimental studies have shown that NRF2 activity can influence CD8+ T cell responses, myeloid-cell polarization, and regulatory T cell function. Consequently, systemic NRF2 inhibition may have complex immunological effects, potentially enhancing antitumor immunity in NRF2-high tumors while simultaneously affecting immune effector cell fitness and function. This therapeutic paradox further supports the need for tumor-selective targeting strategies that preferentially inhibit NRF2 signaling within malignant cells while minimizing unintended effects on antitumor immune responses. In addition, molecular profiling and biomarker-guided patient selection, including assessment of genomic alterations and immune-related features such as PD-L1 expression, may be important for identifying patients most likely to benefit from NRF2-targeted therapeutic approaches.^10,27,34,35

Beyond NRF2-related mechanisms, ICI resistance in HCC is multifactorial and cannot be explained by NRF2 activation alone. Tumor mutational features, antigen presentation defects, exhausted T cells, regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, angiogenesis, gut microbiota, and liver-specific immune tolerance may all contribute to variable ICI responses.^21,23,35 Therefore, future studies should integrate molecular profiling, immune phenotyping, ferroptosis-related biomarkers, and liver function assessment to determine which patients are most likely to benefit from NRF2-based combination strategies.^36,37

FUTURE DIRECTIONS

Future research should focus on validating NRF2 as a clinically useful biomarker and therapeutic target in HCC. Although current evidence supports the involvement of NRF2 in ferroptosis resistance, immune evasion, and impaired ICI response, most findings remain preclinical or translational. Prospective clinical studies are needed to determine whether NRF2 activation status can predict response to PD-1/PD-L1-based therapy, particularly in patients receiving atezolizumab plus bevacizumab, durvalumab plus tremelimumab, or other ICI-based combinations.^38,39

A key priority is the development of standardized biomarkers for NRF2 pathway activation. These may include NFE2L2 or KEAP1 alterations, nuclear NRF2 expression, p62/SQSTM1 accumulation, and NRF2 target genes such as NQO1, HMOX1, SLC7A11, GCLC, GCLM, and GPX4-related antioxidant programs. Because NRF2 activation may interact with immune exclusion and ferroptosis resistance, future biomarker panels should combine NRF2-related markers with CD8+ T cell infiltration, PD-L1 expression, T-effector signatures, COX2/PGE2 signaling, angiogenic signatures, and T cell exhaustion markers.^40,41

From a practical clinical perspective, NRF2 pathway activation can be assessed using several complementary approaches. NFE2L2 and KEAP1 alterations may be identified through next-generation sequencing panels, although these genetic alterations occur in only a subset of HCC cases.³⁶ Immunohistochemical evaluation of nuclear NRF2 expression and p62/SQSTM1 accumulation may provide a more accessible method for routine pathology laboratories. In contrast, assessment of NRF2 target gene expression may require transcriptomic platforms that are not yet widely available in routine clinical practice. Importantly, biomarker interpretation may be complicated by intratumoral heterogeneity, sampling variability, and limited tissue availability, particularly in small biopsy specimens. Therefore, integrated biomarker approaches combining molecular, immunohistochemical, and immune profiling data may be more informative than reliance on a single marker.^23,30,40

Multi-omics approaches may help define NRF2-high HCC subgroups more precisely. Genomic, transcriptomic, proteomic, metabolomic, and epigenomic profiling can identify tumor-intrinsic NRF2 activation, redox adaptation, metabolic rewiring, and ferroptosis-resistant phenotypes.^42,43 Single-cell RNA sequencing and spatial transcriptomics may further clarify how NRF2-active tumor cells interact with immune cells, stromal cells, endothelial cells, and myeloid populations within the HCC tumor microenvironment.^44,45

Pathologic assessment also remains important. Integrating histomorphologic, immunohistochemical, and molecular features may help translate NRF2-related biology into clinically usable biomarkers. In future studies, tissue-based assessment of nuclear NRF2, p62/SQSTM1, SLC7A11, GPX4, COX2, PD-L1, CD8, Forkhead box P3 (FOXP3), and macrophage markers may help identify tumors with immune-cold and ferroptosis-resistant phenotypes.^46,47

Future therapeutic studies should clarify whether NRF2 inhibition, ferroptosis induction, or COX2/PGE2 blockade can safely enhance ICI efficacy in HCC. Because many patients with HCC have underlying cirrhosis or impaired liver function, therapeutic strategies must balance antitumor activity with hepatoprotection. Selective targeting of tumor-specific NRF2 activation, rather than systemic NRF2 suppression, may be necessary to minimize toxicity.^48,49

Clinical trial designs should incorporate molecular stratification and immune phenotyping. Patients with NRF2-high, ferroptosis-resistant, or immune-cold HCC may represent a biologically defined subgroup that could benefit from rational combination strategies. Adaptive trial designs, biomarker-enriched cohorts, and longitudinal sampling may help determine whether NRF2-related biomarkers can predict treatment response, acquired resistance, and toxicity during ICI-based therapy.^50,51

Finally, future studies should consider the broader liver ecosystem. HCC develops in a chronically injured and immunologically tolerant organ, where fibrosis, cirrhosis, viral hepatitis, metabolic dysfunction-associated steatotic liver disease, angiogenesis, and gut-liver axis signaling can influence both tumor biology and immunotherapy response.^52,53 Therefore, NRF2-mediated immune evasion and ferroptosis resistance should be studied within an integrated framework that includes tumor-intrinsic signaling, immune contexture, liver function, and systemic host factors.⁵⁴

CONCLUSION

NRF2 is emerging as an important link between redox adaptation, ferroptosis suppression, and immune resistance in HCC. While physiological NRF2 activity protects hepatocytes from oxidative injury, sustained activation in tumor cells may support survival under therapeutic stress, limit lipid peroxidation-dependent cell death, and contribute to an immunosuppressive tumor milieu. Current evidence suggests that NRF2 activation may reduce sensitivity to immune checkpoint blockade through overlapping mechanisms, including enhanced antioxidant defense, resistance to ferroptosis, impaired innate immune sensing, and inflammatory signaling pathways such as the COX2-PGE2 axis.

These mechanisms provide a rationale for evaluating NRF2-related markers as part of integrated biomarker panels for ICI response. Rather than relying on a single marker, future studies should combine NRF2 pathway activity with ferroptosis-related genes, immune-cell infiltration, PD-1/PD-L1 signaling, angiogenic features, and liver function parameters. Therapeutically, NRF2 inhibition or ferroptosis modulation may improve immunotherapy efficacy, but clinical translation requires caution because NRF2 also has hepatoprotective roles in chronically injured liver tissue.

Collectively, available mechanistic and emerging translational evidence suggests that NRF2-mediated immune escape and ferroptosis resistance may represent a biologically plausible axis contributing to HCC immunotherapy resistance. Prospective translational studies are needed to validate NRF2 as a predictive biomarker, define the patients most likely to benefit from NRF2-targeted combinations, and determine whether selective modulation of this pathway can safely enhance immune checkpoint inhibitor response.

Data Availability

Not applicable