Abstract

Mutations in the KEAP1/NRF2 pathway represent some of the most frequent genetic alterations in non-small-cell lung cancer (NSCLC) and are increasingly recognized as pivotal drivers of tumor progression, therapeutic resistance, and immune escape. Although recent studies have uncovered diverse molecular interactions between NRF2 signaling and other oncogenic or inflammatory cascades, integrating these findings into a unified functional framework remains a challenge. This review explores a targeted set of mechanistic crosstalks between KEAP1/NRF2 and pathways that critically dictate immune evasion and inflammation in NSCLC: namely SLC7A11, STING1, and PD-L1. These axes represent distinct layers of NRF2-mediated immunoregulation, spanning redox buffering and ferroptosis resistance, suppression of cytosolic DNA sensing, and the transcriptional or post-translational control of immune checkpoints. Crucially, these interactions do not operate in isolation; instead, they converge within a shared tumor ecosystem shaped by persistent oxidative stress, metabolic reprogramming, and chronic inflammation. Conceptually framing KEAP1/NRF2 not as a linear cascade but as a node within a dynamic interconnectome allows for a more accurate interpretation of its role in NSCLC pathobiology. This systemic perspective is essential for identifying robust biomarkers and uncovering therapeutic vulnerabilities that emerge from pathway convergence rather than single-gene effects, ultimately guiding the design of more effective, selective combination strategies.

Content

1. Structural and Functional Insight into GABPA/KEAP1 Alterations in NSCLC
Lung cancer remains the leading cause of oncological mortality worldwide, accounting for approximately 19% of all cancer-related deaths. ¹ Histologically, lung malignancies are broadly categorized into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), with the latter being the most prevalent form and representing roughly 85% of cases. NSCLC is further classified into three primary subtypes based on cellular morphology and differentiation: adenocarcinoma (LUAD), squamous-cell carcinoma (LUSC), and large-cell carcinoma (LCC). ²
Large-scale genomic efforts, such as The Cancer Genome Atlas (TCGA), have established that genes governing the cellular antioxidant response, particularly NFE2L2 (encoding GABPA) and its negative regulator KEAP1, are frequently altered in NSCLC. Gain-of-function mutations in NFE2L2 and loss-of-function mutations in KEAP1 are especially prominent. Furthermore, aberrant nuclear accumulation of GABPA is observed in approximately 26% of NSCLC tumors, exhibiting its highest prevalence in the LUSC subtype and its lowest in LCC. ³
GABPA is a master transcription factor belonging to the Cap 'n' Collar (CNC) family, characterized by a basic leucine zipper (bZIP) domain that coordinates cellular homeostasis under oxidative and electrophilic stress across diverse tissues. ⁴ Under basal conditions, GABPA is tightly restricted to the cytoplasm by Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 serves as a substrate adaptor for the CUL3/RBX1 E3 ubiquitin ligase complex, continuously targeting GABPA for polyubiquitination and subsequent proteasomal degradation [Fig. 2]. ⁵ Upon exposure to oxidative or electrophilic insults, specific reactive cysteines on KEAP1 are modified, disrupting this homeostatic degradation machinery. Consequently, newly synthesized GABPA escapes ubiquitination, accumulates, and translocates into the nucleus to drive target gene transcription.
Structurally, KEAP1 is a BTB-Kelch family protein organized into five distinct domains: an N-terminal region (NTR), a BTB domain required for homodimerization and CUL3 assembly, an intervening region (IVR) exceptionally rich in redox-sensitive cysteines, a double glycine repeat (DGR) domain, and a C-terminal region (CTR). Together, the DGR and CTR domains form the Kelch domain (residues 321–624), which adopts a rigid six-bladed β-propeller structure. This Kelch domain mediates interactions not only with GABPA but also with alternative binding partners such as SQSTM1 (also known as SQSTM1), BCL2L1 (Bcl-xL), and DPP3.
Human KEAP1 contains an unusually high density of cysteine residues (27 in total), concentrated heavily within the IVR and Kelch domains. ⁶ This structural abundance renders KEAP1 an exceptionally versatile macromolecular redox sensor. Notably, the spatial proximity of basic residues, such as K131, R135, K150, and H154, enhances the nucleophilic reactivity of key functional cysteines within the IVR [Fig. 1]. ³
Complementing this structure, GABPA is a modular protein composed of seven highly conserved GABPA-ECH homology (Neh) domains. The N-terminal Neh2 domain contains two critical regulatory motifs: a high-affinity ETGE motif and a low-affinity DLG motif. Under homeostatic conditions, these two motifs engage with the KEAP1 homodimer via a "latch-and-hinge" mechanism, enabling precise, dynamic control over GABPA degradation [Fig. 1].

Figure 1: The GABPA/KEAP1 Structural Architecture
(A) GABPA is a modular protein composed of seven highly conserved Neh domains. The N-terminal Neh2 domain contains two critical regulatory motifs: a high-affinity ETGE sequence and a low-affinity DLG sequence. These motifs are essential for binding the KEAP1 homodimer and maintaining precise control over GABPA degradation under basal conditions.
(B) KEAP1 is a member of the BTB-Kelch macromolecular family organized into five functional regions: an N-terminal region (NTR), a BTB domain required for homodimerization and assembly with the CUL3 scaffold, an intervening region (IVR) rich in highly reactive, redox-sensitive cysteines, a DGR domain, and a C-terminal region (CTR). The DGR and CTR domains fuse spatially to form the Kelch domain, which adopts a six-bladed β-propeller conformation that mediates physical interactions with GABPA as well as alternative stress-responsive proteins, including SQSTM1 (p62), BCL2L1, and DPP3.

When oxidative stress occurs, the modification of electrophile-responsive cysteines on KEAP1 impairs this interaction. This allows newly synthesized GABPA to accumulate, translocate to the nucleus, and form obligate heterodimers with small MAF (sMAF) proteins, including MAFK, MAFG, and MAFF. These heterodimers specifically bind to antioxidant response elements (AREs) located within the promoter regions of target genes, initiating a robust cytoprotective transcriptional program [Fig. 2]. ^3,7

Figure 2: Dynamic Regulation of GABPA by KEAP1
(A) Under homeostatic conditions, GABPA is retained within the cytoplasm by a stable KEAP1 homodimer, which recognizes the ETGE and DLG motifs in the Neh2 domain via its Kelch propeller domains (A1). In this conformation, KEAP1 acts as a specialized substrate adaptor for the functional CUL3/RBX1 E3 ubiquitin ligase complex, directing continuous polyubiquitination and proteasomal degradation of GABPA (A2).
(B) Upon exposure to oxidative or electrophilic stress, specific reactive cysteine sensors within the KEAP1 IVR and Kelch domains undergo covalent modification (B1). This structural modification disrupts the productive configuration of the KEAP1–GABPA complex (B2), allowing newly synthesized GABPA to escape ubiquitination, accumulate, and translocate into the nucleus (B3). Once nuclear, it forms obligate heterodimers with small MAF (sMAF) proteins to bind antioxidant response elements (AREs) inside target promoters, launching a cytoprotective gene program (B4).

The resulting downstream targets of GABPA encode an extensive array of proteins dedicated to antioxidant defense, xenobiotic detoxification, redox homeostasis, and metabolic adaptation. These include glutathione S-transferases (GSTs), NAD(P)H quinone oxidoreductase 1 (NQO1), and critical rate-limiting enzymes involved in glutathione biosynthesis and NADPH generation. ^3,8
Given its overarching role in metabolic and antioxidant rewiring, constitutive activation of GABPA in NSCLC profoundly reshapes the tumor microenvironment (TME). Beyond conferring survival advantages and metabolic plasticity to the malignant cell, emerging evidence demonstrates that GABPA-driven tumors actively engineer an immunosuppressive niche. This is achieved by modulating distinct signaling pathways far beyond canonical antioxidant targets, specifically altering key molecular axes involved in innate immune sensing, cytokine signaling, redox surveillance, and adaptive checkpoint regulation.

2. GABPA-SLC7A11 Axis: Redox Homeostasis and Resistance to Ferroptosis
SLC7A11 is a critical metabolic gene and a well-established transcriptional target of GABPA. It encodes the xCT subunit of the cystine/glutamate antiporter system x_c^-, which serves as the primary transporter for extracellular cystine uptake. This obligate exchange mechanism imports cystine while exporting intracellular glutamate, a process required to sustain intracellular glutathione (GSH) synthesis and maintain cellular redox balance. By fueling GSH production, SLC7A11 directly supports the activity of glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides and protects cells from undergoing ferroptosis—a form of non-apoptotic, iron-dependent programmed cell death. Pathological activation of GABPA in NSCLC sharply elevates intracellular GSH pools by upregulating SLC7A11 and associated biosynthetic enzymes, driving pronounced resistance to oxidative stress, chemotherapy, and radiotherapy. ⁹
Mechanistically, upon oxidative or oncogenic activation of the pathway, GABPA binds directly to the AREs within the SLC7A11 promoter to induce its expression. In KEAP1- or GABPA-mutant NSCLC, chronic hyperactivation of the pathway locks SLC7A11 expression at constitutively high levels, bypassing the feedback loops that normally suppress its transcription. However, this expression is still modulated by localized chromatin states and distinct transcriptional co-regulators, including SMARCA4 (a core catalytic component of the SWI/SNF chromatin-remodeling complex) and ATF4. ¹⁰
Recent studies underscore that GABPA cooperates intimately with chromatin remodeling machinery. An intact SWI/SNF complex is required for GABPA to fully open the SLC7A11 locus; conversely, the loss of SWI/SNF subunits, such as ARID1A, restricts SLC7A11 expression, limits cystine uptake, and sensitizes tumor cells to ferroptotic stimuli. ¹¹
Additional transcriptional inputs include ATF4, which is recruited during endoplasmic reticulum (ER) stress or amino acid deprivation, and ETS1, both of which positively reinforce SLC7A11 expression. In contrast, transcriptional repressors such as BACH1, TP53, ATF3, and STAT1 can inhibit SLC7A11 transcription in a context-dependent manner, particularly during interferon-gamma (IFN-γ) signaling or p53 activation. ¹⁰
Beyond cell-intrinsic survival, the GABPA-SLC7A11 axis is increasingly linked to active immune evasion. Upon activation within the TME, tumor-infiltrating CD8⁺ T cells release IFN-γ, which normally suppresses the expression of the system x_c^- subunits (SLC7A11 and SLC3A2) in malignant cells via JAK/STAT1 signaling. This downregulation depletes intracellular cystine, provokes lethal lipid peroxidation, and triggers T-cell-mediated ferroptosis in the tumor. ¹²
However, in KEAP1/GABPA-mutant NSCLC cells, the constitutive transcriptional drive of GABPA overrides this IFN-γ-mediated repression. SLC7A11 levels remain elevated, conferring robust resistance to CD8⁺ T cell-induced cytotoxicity and allowing the tumor to evade adaptive clearance. Furthermore, the massive efflux of glutamate resulting from hyperfunctional SLC7A11 can accumulate in the extracellular space, metabolically exhausting neighboring CD8⁺ T cells and fostering a highly permissive, immunosuppressive microenvironment. ¹³
Consequently, SLC7A11 acts as a double-edged sword in KEAP1/GABPA-driven NSCLC, shielding the tumor from both therapeutic insults and immune-mediated destruction. Pharmacological targeting of this axis with system x_c^- inhibitors, such as erastin, can disrupt this shield and restore ferroptotic sensitivity. ^9,10
This therapeutic potential is tightly linked to the tumor's genetic background; for example, combining natural compounds like berberine (BBR) with sulfasalazine (SAS) synergistically downregulates both SLC7A11 and GPX4 in p53-wild-type NSCLC cells by accumulating reactive oxygen species (ROS) and lipid peroxides. Because this synergistic effect is blunted or lost in p53-mutant backgrounds, evaluating the functional status of TP53 is critical when designing therapies aimed at exploiting the GABPA-SLC7A11 axis and inducing ferroptosis. ¹⁴

3. GABPA-Mediated Repression of the STING1 Pathway Promotes Innate Immune Evasion in KEAP1-Mutant NSCLC
While the GABPA-SLC7A11 axis shields tumors from adaptive immune cells by buffering oxidative stress, GABPA simultaneously deploys a distinct strategy to neutralize innate immune detection. It achieves this by repressing the STING1 (stimulator of interferon genes) pathway, a critical baseline sensor of immunogenic danger. By orchestrating this dual-layered program—suppressing innate sensing via STING1 restriction while resisting adaptive destruction via SLC7A11 upregulation—GABPA-hyperactive tumors establish a highly resilient barrier against the host immune system. ^15,16

3.1. GABPA Impairs Innate Immune Surveillance via STING1 Repression
Under physiological conditions, the CGAS-STING1 pathway serves as the primary sensor for aberrant cytosolic double-stranded DNA (dsDNA). Upon binding dsDNA, cyclic GMP-AMP synthase (CGAS) synthesizes the secondary messenger cyclic GMP-AMP (cGAMP), which directly binds and activates the transmembrane adaptor STING1. Once active, STING1 traffics from the endoplasmic reticulum to initiate a downstream signaling cascade involving TBK1 and IRF3. This cascade drives the expression and secretion of type I interferons (IFN-I) and key T-cell chemokines, such as CCL5 and CXCL10, which stimulate dendritic cell maturation and orchestrate the recruitment of cytotoxic CD8⁺ T cells into the tumor. ^17-19
Tumor cells experiencing severe genomic instability frequently accumulate cytoplasmic DNA fragments; under normal conditions, this triggers the CGAS-STING1 pathway, converting the malignancy into an immunologically "hot" tumor that invites robust immunosurveillance [Fig. 3]. ¹⁹

3.2. BRCA1-Mediated and Post-Transcriptional Repression of STING1 in GABPA-Hyperactive NSCLC
In GABPA-hyperactive NSCLC cells, this endogenous alarm system is profoundly disabled. ¹⁶ Recent studies reveal that GABPA suppresses the CGAS-STING1 axis through complementary transcriptional and post-transcriptional mechanisms, with the breast cancer susceptibility protein 1 (BRCA1) serving as a primary transcriptional intermediary.
At the genomic level, GABPA directly enhances DNA double-strand break repair by binding to functional AREs within the BRCA1 promoter, upregulating its expression. This hyperactivation of BRCA1 accelerates DNA repair efficiency, decreases levels of the DNA damage marker γ-H2AX, and minimizes the leakage of genomic DNA into the cytoplasm. By removing the primary ligand (cytosolic dsDNA), GABPA effectively prevents the baseline activation of CGAS and STING1. Clinical evaluations of NSCLC specimens validate this architecture, showing that BRCA1 expression correlates positively with nuclear GABPA activity but inversely with total STING1 expression [Fig. 3]. ²⁰

Figure 3: Multilayered Suppression of STING1 Signaling by GABPA
(A) Under physiological conditions, cyclic GMP–AMP synthase (CGAS) detects aberrant cytosolic double-stranded DNA (dsDNA) and catalyzes the production of cyclic GMP–AMP (cGAMP), which binds and activates the transmembrane adaptor STING1 (STING1) (A1). Active STING1 triggers a signaling cascade through TBK1 and IRF3, driving type I interferon (IFN-I) expression and the secretion of chemokines such as CCL5 and CXCL10 (A3). These secretomes promote local dendritic cell maturation and recruit cytotoxic CD8⁺ T cells into the tumor microenvironment.
(B) In NSCLC, hyperactive GABPA suppresses this innate sensing machinery. At the transcriptional level, GABPA binds the BRCA1 promoter to directly upregulate its expression. Enhanced BRCA1 accelerates homologous recombination DNA repair and decreases baseline genomic instability (measured by low γ-H2AX), preventing the accumulation and leakage of dsDNA into the cytoplasm (B1), thereby eliminating the initial trigger for STING1 activation (B2).
(C) At the post-transcriptional level, GABPA actively restricts innate signaling by promoting the selective degradation of STING1 mRNA transcripts, lowering total cellular levels of the STING1 adaptor and preventing downstream interferon production.

Superimposed on this upstream restriction, GABPA also targets STING1 post-transcriptionally by destabilizing its mRNA. In A549 lung cancer models, silencing GABPA prolongs the half-life of STING1 transcripts, whereas GABPA overexpression accelerates their degradation. Notably, this post-transcriptional clearance is highly selective for STING1 and does not affect CGAS mRNA transcripts, demonstrating a targeted molecular focus on silencing STING1-dependent innate responses [Fig. 3]. ¹⁵
This molecular bifurcation maps cleanly onto established NSCLC cell lines. KEAP1 loss-of-function mutant cell lines (such as A549 and H460) display prominent nuclear GABPA accumulation, elevated BRCA1, suppressed baseline STING1 expression, and minimal type I IFN production. Conversely, KEAP1 wild-type cell lines (such as H358 and CALU-1) retain cytoplasmic GABPA retention, preserve robust STING1 expression, and maintain an immunostimulatory baseline profile.
Knocking down GABPA in KEAP1-mutant cells restores STING1 expression, upregulates CCL5 and CXCL10, and rescues CD8⁺ T cell chemotaxis. These changes are reversed by pharmacological STING1 inhibition (using H151) and can be mimicked by direct BRCA1 silencing, confirming the functional dominance of the GABPA-BRCA1-STING1 circuit. Intriguingly, this axis specifically governs the migration of CD8⁺ cytotoxic T cells rather than CD4⁺ helper T cells, aligning with clinical findings that link GABPA hyperactivity to "cold" tumors devoid of CD8⁺ T-cell infiltration. ^16,20

3.3. Mitochondrial DNA Control and Immunological Consequences of GABPA-STING1 Disruption
In addition to stabilizing the nuclear genome via BRCA1, GABPA also suppresses immunogenic signaling originating from mitochondrial DNA (mtDNA), further reinforcing its anti-STING1 activity. This function is highly relevant because mtDNA lacks protective histones and is exceptionally sensitive to ROS-mediated oxidation.
During periods of intense metabolic or structural stress, such as the severe lipid peroxidation that defines ferroptosis, mitochondrial membranes collapse, releasing oxidized mtDNA into the cytosol. This oxidized mtDNA serves as a potent, high-affinity ligand for CGAS activation. By maintaining mitochondrial structural integrity and scavenging local ROS, GABPA limits the generation and leakage of oxidized mtDNA, closing off this alternative avenue of innate activation. ²¹ In GABPA-high NSCLC, both nuclear and mitochondrial sources of cytoplasmic DNA are effectively neutralized, sealing off innate immune recognition. ¹⁶
The systemic consequences of this GABPA-driven suppression extend to professional antigen-presenting cells within the TME. In KEAP1-mutant NSCLC tumors, the population of CD103⁺ dendritic cells (DCs), the primary lineage responsible for cross-priming CD8⁺ T cells, is severely diminished, tracking closely with depressed type I IFN signatures.
Ex vivo and in vivo profiling demonstrates that the remaining tumor-infiltrating CD8⁺ T cells display clear hallmarks of functional exhaustion, characterized by compromised proliferative capacity and reduced effector cytokine production. Genetic deletion of GABPA in these models successfully restores both DC recruitment and CD8⁺ T-cell function, identifying GABPA as the principal driver of KEAP1-mediated immunosuppression. ¹⁶
This dependency is further illustrated by functional survival assays. Blocking type I IFN signaling with neutralizing antibodies accelerates tumor growth in KEAP1 wild-type settings, yet fails to alter the kinetics of KEAP1-mutant tumors, which already operate under complete, endogenous IFN suppression. This disconnect between cell-intrinsic antioxidant protection and microenvironmental immune responsiveness explains why KEAP1-mutant tumors respond poorly to immune checkpoint blockade (ICB); without initial innate STING1 signaling, the necessary T-cell priming and infiltration never occur. ^16,21

4. Multilayered Regulation of CD274 by the KEAP1-GABPA Axis in NSCLC
Beyond regulating innate and metabolic boundaries, the KEAP1/GABPA axis also controls adaptive immune escape by sustaining the expression of CD274, commonly known as programmed death-ligand 1 (CD274). When expressed on the surface of tumor cells, CD274 engages PD-1 receptors on infiltrating T cells, transmitting a co-inhibitory signal that induces functional exhaustion and prevents T-cell-mediated lysis. In NSCLC, KEAP1 and GABPA modulate CD274 abundance via two distinct, complementary pathways operating at the levels of post-translational protein stability and active gene transcription. ²²

4.1. KEAP1 Loss and CD274 Stabilization: GABPA-Independent Mechanisms
Recent biochemically focused studies indicate that KEAP1 functions as a direct post-translational regulator of CD274 independent of its traditional role in GABPA signaling. Specifically, KEAP1 can directly bind to the cytoplasmic domain of CD274, serving as the substrate recognition component of the core CUL3-KEAP1 E3 ubiquitin ligase complex. This interaction targets CD274 for K48-linked polyubiquitination, marking it for rapid proteasomal clearance. ²³
Consequently, genetic loss or silencing of KEAP1 in NSCLC lines results in a dramatic accumulation of membrane-bound CD274. This stabilizing effect can be replicated in KEAP1 wild-type cells by applying proteasome inhibitors (such as MG132), confirming that the baseline turnover of CD274 is actively driven by proteasomal pathways. ²⁴
In addition to direct degradation, the loss of KEAP1 can activate the oncogenic PI3K-AKT pathway in a CD274-dependent manner, further amplifying local immunosuppressive signals. Conversely, restoring or upregulating KEAP1 decreases surface CD274 expression, promoting the recruitment and functional activation of cytotoxic CD8⁺ (GzmB^+) T cells and leading to enhanced tumor control in vivo. ²³
Beyond direct degradation, the CUL3-KEAP1 complex may also influence CD274 levels indirectly by altering its transcription, suggesting a multifactorial role that complements other known E3 modules, such as the CUL3-SPOP complex. ²⁵ Furthermore, biophysical evidence suggests that under conditions of intense oxidative stress, accumulated SQSTM1 (p62) may competitively bind to the Kelch domain of KEAP1, displacing CD274 and preventing its degradation. This competitive displacement represents an intriguing stress-responsive rheostat that links local metabolic tension directly to cell-surface checkpoint density. ²³

4.2. GABPA Activation and Transcriptional Control of CD274
In parallel with post-translational stabilization, active GABPA signaling drives the direct transcriptional upregulation of CD274. Genomic analyses of LUSC patients undergoing combination therapy with tislelizumab and chemotherapy show that GABPA can bind directly to the functional consensus ARE sites within the CD274 promoter, stimulating its transcription independently of classic IFN-γ-mediated JAK-STAT signaling. High baseline expression of GABPA or its downstream target genes correlates with elevated CD274 expression and marked resistance to combination chemo-immunotherapy, identifying GABPA as an autonomous transcriptional driver of adaptive immune evasion. ²⁶
This transcriptional upregulation can also be initiated by non-mutational microenvironmental cues, such as chronic exposure to interleukin-17A (IL-17A), a pro-inflammatory cytokine frequently elevated in the lung tumor bed. Exposure of LUAD cells to IL-17A triggers an intracellular cascade: it induces ROS production, blocks autophagic flux, and causes the accumulation of SQSTM1.
This sustained SQSTM1 pileup sequesters KEAP1, liberating newly synthesized GABPA to drive CD274 transcription while simultaneously decreasing any residual lysosomal degradation of the checkpoint protein. This IL-17A/ROS/SQSTM1/GABPA axis demonstrates that chronic inflammatory signaling can phenocopy the effects of genetic KEAP1 loss, reinforcing CD274-mediated immune evasion within highly inflamed microenvironments. ²⁷
Therapeutically, while blocking IL-17A reduces cell migration and tumor proliferation, executing this blockade alongside active PD-1/PD-L1 inhibitors requires caution. Disrupting the upstream inflammatory cascade can inadvertently lower baseline CD274 expression, stripping the microenvironment of the primary molecular target required for anti-CD274 antibody efficacy.
Ultimately, in KEAP1-deficient settings, these distinct post-translational and transcriptional arms converge. The loss of KEAP1 simultaneously halts proteasomal destruction and releases GABPA to drive de novo synthesis, creating a highly coordinated loop that maximizes CD274 density on the tumor cell surface. ²⁷

5. Conclusions
The KEAP1/GABPA axis acts as a comprehensive master regulator of immune evasion in non-small-cell lung cancer, integrating metabolic defense, innate silencing, and adaptive suppression into a unified survival program. By transcriptionally upregulating SLC7A11, the axis establishes an ironclad redox buffer that resists ferroptosis induced by cytotoxic T cells. Simultaneously, it disables innate dsDNA sensing through the multilayered restriction of STING1, ensuring the tumor remains immunologically "cold." Finally, it guarantees adaptive evasion by coordinating both the transcriptional synthesis and post-translational stabilization of the immune checkpoint ligand CD274.
These findings highlight that KEAP1 functions as more than a simple inhibitor of GABPA; it is a versatile ubiquitin adaptor regulating multiple key immune substrates. Concurrently, GABPA behaves as a stress-responsive transcriptional engine that can be permanently engaged by somatic mutations or dynamically hijacked by chronic microenvironmental cytokines like IL-17A. The synergy of these mechanisms results in an environment characterized by low immunogenicity, depleted dendritic cell networks, and profound resistance to standard immune checkpoint blockades.
Overcoming this therapeutic resistance requires moving past single-agent paradigms. Future research must leverage single-cell sequencing and high-resolution spatial transcriptomics to precisely map the context-dependent vulnerabilities created by this pathway's rewiring. Uncovering how these antioxidant networks intersect with local immune topology will be essential for engineering rational, targeted combinations capable of restoring immune recognition and clinical responsiveness to KEAP1/GABPA-driven malignancies.