E74-like E26 transformation-specific transcription factor 3 in gastric cancer: Functions, mechanisms, and clinical translation - unresolved issues

Abstract

Gastric cancer is one of the most common malignancies worldwide, with gastric adenocarcinoma accounting for more than 90% of all cases. Despite the advances in treatment, the prognosis for patients with advanced disease remains extremely poor, highlighting the urgent need for novel biomarkers and therapeutic targets. E26 transformation-specific (ETS) transcription factor E74-like ETS transcription factor 3 (ELF3) exhibits context-dependent regulatory functions in epithelial-derived malignancies, acting either as an oncogene or a tumor suppressor, depending on the cellular context. A recent study on gastric cancer was the first to systematically delineate the expression profile and clinical significance of ELF3, proposing a dual mechanism that may contribute to tumor progression. In the broader context of ELF3 research, the present opinion review focused on three core issues: (1) Is the function of ELF3 consistent between gastric cancer and other tumors; (2) To what extent does present evidence support the dual-action model of ELF3 in regulating CDH1 and CXCL11; and (3) What are the clinical translational prospects of ELF3 as both a biomarker and a therapeutic target? By systematically reviewing the available evidence and identifying key research gaps, the present study aims to provide a clear analytical framework for future investigations, ultimately translating ELF3 biology into clinical practice.

Key Words: Gastric cancer; E74-like E26 transformation-specific transcription factor 3; Immune evasion; Tumor microenvironment; Prognostic biomarker; Targeted therapy

Core Tip: E74-like E26 transformation-specific transcription factor 3 (ELF3) exhibits context-dependent functions in gastric cancer. Present evidence supports its pro-tumorigenic role through the regulation of epithelial-mesenchymal transition and immune evasion, although functional validation remains required. Patients with high ELF3 expression present with a “cold” tumor phenotype that may limit the responsiveness to immunotherapy. Future research should focus on completing the chain of functional validation and systematically evaluating existing ELF3-targeting compounds in gastric cancer models, particularly in combination with immune checkpoint inhibitors.

INTRODUCTION

Gastric cancer is one of the most common malignancies worldwide, and the fourth leading cause of cancer-related mortality[1]. According to the GLOBOCAN 2020 data, there are over one million new cases of gastric cancer and approximately 769000 deaths annually[1]. Among these, gastric adenocarcinoma (STAD) is the predominant histological type, accounting for more than 90% of all gastric cancer cases[2,3]. Despite the significant advances in surgical techniques, neoadjuvant chemotherapy, and targeted therapies in recent years, the prognosis for patients with advanced (stage IV) disease remains extremely poor due to high heterogeneity and the complex molecular mechanisms of gastric cancer, with a 5-year survival rate of only 16.4%[4]. Therefore, the identification of novel, reliable prognostic biomarkers and effective therapeutic targets is an urgent priority in present gastric cancer research.

The E26 transformation-specific (ETS) transcription factor family is a highly evolutionarily conserved protein family that regulates diverse biological processes, including cell proliferation, differentiation, apoptosis, migration, and angiogenesis, by binding to specific DNA sequences in the promoter regions of target genes[5]. The dysregulated expression or function of ETS family members has been confirmed to play critical roles in the initiation and progression of various malignancies[6]. E74-like ETS transcription factor 3 (ELF3), which is an important member of the ETS family, was initially found to be highly expressed in epithelial tissues, wherein it participates in regulating epithelial cell differentiation and homeostasis[7,8]. Recent studies have indicated that the function of ELF3 is distinctly tissue-dependent: In colorectal cancer, prostate cancer, and hepatocellular carcinoma, ELF3 has been confirmed to exert pro-tumorigenic effects by regulating key molecules, such as β-catenin, nuclear factor-κB and ZEB1, to drive tumor progression[9-12]. However, its precise function, mechanism of action, and clinical value in gastric cancer have long remained systematically unclarified.

The tumor microenvironment (TME) has garnered increasing attention for its role in tumor progression and therapeutic response[13]. Tumor-infiltrating immune cells are key determinants of tumor fate, with the infiltration level of CD8+ cytotoxic T lymphocytes (CTLs) positively correlated with the prognosis in various solid tumors[14,15]. Tumor cells can remodel the TME through multiple mechanisms to establish an immunosuppressive state, thereby evading host immune attack[16]. Recent studies have suggested that transcription factors not only regulate the tumor cells themselves, but also actively shape an immunosuppressive TME by influencing chemokine expression[17]. For example, ELK3, which is a member of the same ETS family as ELF3, has been reported to negatively correlate with regulatory T cell infiltration in gastric cancer[18]. In bladder cancer, ELF3 has been identified as a key transcriptional regulator of an anti-apoptotic subpopulation, interacting with stromal cells through CXCL and other signaling pathways[19]. In cholangiocarcinoma, ELF3 has been identified as a promising diagnostic marker, with its expression significantly increased in tumor tissues, and its regulatory networks linked to immune cell regulation and cell adhesion[20]. A recent study in gastric cancer integrated multiple public database analyses, and validated findings in an independent cohort of 100 STAD patients, systematically delineating for the first time the expression profile and clinical significance of ELF3 in gastric cancer[21]. The results revealed that ELF3 is significantly overexpressed in gastric cancer tissues, and is an independent risk factor for poor overall survival. More importantly, this study proposed a dual mechanism by which ELF3 may drive gastric cancer progression: On one hand, it may promote epithelial-mesenchymal transition (EMT) via CDH1 repression; on the other hand, it may impair CTL recruitment via CXCL11 inhibition (Figure 1).This discovery elevates ELF3 from a mere prognostic marker to a key molecule that links tumor aggressiveness with immune microenvironment remodeling, while also raising a series of questions worthy of in-depth investigation. In addition, a multi-omics analysis of gastric cancer peritoneal metastasis revealed that ELF3 mutations in primary tumors are associated with increased risk of peritoneal dissemination, highlighting the potential role of ELF3 in metastatic progression[22].

Figure 1 Schematic illustration of the dual role of E74-like E26 transformation-specific transcription factor 3 in gastric cancer progression. A: E74-like E26 transformation-specific transcription factor 3 (ELF3) binds the CDH1 promoter to inhibit E-cadherin expression, inducing epithelial-mesenchymal transition; B: ELF3 binds the CXCL11 promoter to inhibit its expression, impairing CD8+ T cell recruitment. This figure is based on the model proposed by Sun et al[21], which presently has support from binding evidence and correlational data, but functional validation remains to be supplemented. The diagram is drawn by Figdraw (www.figdraw.com). EMT: Epithelial-mesenchymal transition; ELF3: E74-like E26 transformation-specific transcription factor 3; CTL: Cytotoxic T lymphocyte.

Based on these considerations, the present study focused on three core issues: (1) Is the function of ELF3 consistent between gastric cancer and other tumors; (2) In the dual mechanism of ELF3 in regulating CDH1 and CXCL11 in gastric cancer, does present evidence support this model; and (3) For the clinical translational prospects of ELF3, can gastric cancer patients benefit from it? By systematically reviewing available evidence, and identifying key controversies and research gaps, the present study aims to provide a clear analytical framework for the future development of ELF3 research in gastric cancer.

IS THE FUNCTION OF ELF3 CONSISTENT BETWEEN GASTRIC CANCER AND OTHER TUMORS?

When exploring the biological function of any molecule, the primary question often asked is whether it exhibits universality across different tumors. For ELF3, this question is particularly pertinent: Does its behavior in gastric cancer align with observations in other tumors?

Through the integrated analysis of multiple public databases and its validation in an independent clinical cohort of 100 STAD patients, Sun et al[21] were the first to systematically characterize the expression profile and clinical significance of ELF3 in gastric cancer. Additionally, Li et al[23] provided functional evidence that ELF3 directly binds to the IRF6 promoter and positively regulates IRF6 expression in gastric cancer cells, further supporting the transcriptional regulatory role of ELF3 in gastric cancer. Their study revealed that ELF3 is significantly overexpressed in gastric cancer tissues, and that its expression level is negatively correlated with patient overall survival, with the multivariate analysis indicating a more than 4-fold increase in risk of death in patients with high ELF3 expression. Mechanistic studies have further revealed that ELF3 directly binds the CDH1 gene promoter, inhibiting E-cadherin transcription, and thereby inducing EMT. Concurrently, ELF3 inhibits the CXCL11 expression, impairing CTL recruitment, and mediating immune evasion[21]. These findings are supported by other studies. Through the analysis of the TCGA database, studies found that ELF3 mRNA expression levels are relatively high in gastric cancer, and correlate with the expression of other gastric cancer-related transcription factors, such as HNF4A and GATA6[24,25]. Li et al[26] discovered that ELF3-regulated lncRNA UBE2CP3 drives gastric cancer metastasis through the miR-138-5p/ITGA2 axis. Song et al[27] confirmed that ELF3-AS1 promotes gastric cancer progression by binding to hnRNPK, and regulating the CCL20 expression. Together, these studies suggest a pro-tumorigenic role, although direct functional evidence remains limited.

However, when expanding the view to other tumors, the functional landscape of ELF3 becomes more complex. Table 1 systematically summarizes the functional roles of ELF3 across various tumor types, clearly illustrating this diversity. In colorectal cancer, Wang et al[9] found that ELF3 promotes tumor progression by driving β-catenin transactivation, with its high expression associated with poor patient prognosis. In hepatocellular carcinoma, Zheng et al[10] reported that ELF3 indirectly induces EMT by protecting ZEB1 from miR-141-3p-mediated silencing. In non-small cell lung cancer, Wang et al[28] reported that ELF3 activates the PI3K/Akt and ERK pathways to promote cell growth and metastasis. Furthermore, the role of ELF3 in maintaining epithelial phenotype has been demonstrated[29]. In endometrial cancer, Liu et al[30] discovered that ELF3 promotes EMT by inhibiting TPM1 transcription. In papillary thyroid cancer, Tao et al[31] identified ELF3 as a core factor in a lymph node metastasis-related gene expression program using single-cell sequencing.

Table 1 Summary of E74-like E26 transformation-specific transcription factor 3 functions across different tumor types[9-12,19,21,24-28,30-35,37,40-52].

Tumor type	Functional role	Key findings
Gastric cancer[21]	Pro-tumorigenic	ELF3 is significantly overexpressed, an independent risk factor for poor overall survival; directly binds CDH1 promoter to inhibit E-cadherin, inducing EMT; directly binds CXCL11 promoter to inhibit expression, impairing CTL recruitment, mediating immune evasion
Gastric cancer[39]	Potentially tumor-suppressive	FZD5 inhibits ZEB1 expression and prevents EMT through PKC-ELF3 axis; FZD5 and ELF3 associated with longer survival
Gastric cancer[26]	Regulatory relationship	ELF3 directly represses lncRNA UBE2CP3; UBE2CP3 promotes gastric cancer metastasis via miR-138-5p/ITGA2 axis
Gastric cancer[27]	Regulatory relationship	ELF3-AS1 promotes gastric cancer progression by binding hnRNPK and regulating CCL20 expression
Gastric cancer[24,25]	Regulatory relationship	ELF3 mRNA is highly expressed in gastric cancer, correlates with expression of transcription factors such as HNF4A and GATA6
Colorectal cancer[9]	Pro-tumorigenic	Drives β-catenin transactivation, promotes proliferation and invasion; high expression is associated with poor prognosis
Colorectal cancer[41]	Pro-tumorigenic	High mRNA and protein expression associated with increased recurrence rate and shortened relapse-free survival in stage II patients; an independent poor prognostic factor
Colorectal cancer[11]	Therapeutic targeting	In KRAS (G13D)-mutant colorectal cancer, ELF3 core transcription factor of HER2-ELF3-KRAS axis, drives progression and confers cetuximab resistance by upregulating KRAS; small molecule YK1 disrupts ELF3-MED23 interaction, restores drug sensitivity
Hepatocellular carcinoma[10]	Pro-tumorigenic	Increased expression associated with poor prognosis; promotes proliferation, migration, invasion; binds miR-141-3p promoter to inhibit its expression, protecting ZEB1 from silencing and inducing EMT
Non-small cell lung cancer[28]	Pro-tumorigenic	mRNA and protein upregulated, associated with overall survival; ELF3 silencing inhibits proliferation and metastasis; activates PI3K/Akt and ERK pathways
Non-small cell lung cancer[42]	Regulatory relationship	miR-320a-3p directly binds ELF3 mRNA 3'UTR, downregulates ELF3 expression, inhibits proliferation, migration, invasion via PI3K/Akt pathway
Lung adenocarcinoma[37]	Pro-tumorigenic (lineage-specific)	Focal amplification at 1q32.1, gene dosage and promoter hypomethylation affect locus; oncogene in lung adenocarcinoma but not in lung squamous cell carcinoma; required for tumor growth
Endometrial cancer[30]	Pro-tumorigenic	ELF3 knockdown inhibits proliferation and colony formation, promotes E-cadherin expression, inhibits N-cadherin and vimentin, reduces EMT; ELF3 promotes EMT and tumor development by binding TPM1 promoter and inhibiting its transcription
Papillary thyroid cancer[31]	Pro-tumorigenic	Core gene in EMT-related gene expression program GEP3, drives tumor invasion and angiogenesis; ELF3 knockdown inhibits EMT and angiogenesis, reduces cell migration and invasion
Biliary tract cancer[32]	Tumor-suppressive	Directly inhibits ZEB2, upregulates CGN maintaining cell junctions; regulates ALOX5 and CXCL16 affecting immune response; conditioned medium from ELF3-overexpressing cells significantly enhances NK cell and CD8+ T cell migration
Ovarian cancer[33]	Tumor-suppressive	Downregulated expression associated with shortened survival; overexpression inhibits proliferation and anchorage-dependent growth; increases epithelial markers, decreases mesenchymal markers
Ovarian cancer[43]	Pro-tumorigenic (context-specific)	Highly expressed under hypoxic conditions; acts as a transcription factor for IGF1, promotes IGF1 and VEGF secretion, enhances endothelial cell proliferation, migration, and angiogenesis
Bladder urothelial carcinoma[34]	Tumor-suppressive	Downstream component of WNT7B/FZD5 signaling, transcriptionally regulates NOTCH1, exerts tumor-suppressive effects
Bladder cancer[44]	Transcriptional regulator	Single-cell analysis identified anti-apoptotic tumor subpopulation; ELF3 together with CEBPB, EGR1, EZH2 acts as a key transcriptional regulator, interacts with immune and stromal cells via FGF, CXCL, VEGF signaling pathways to promote tumor progression
Bladder cancer[45]	Functional alteration	ELF3 mutation (14%) leads to truncated protein, altering regulatory interactions and upregulating neighboring gene PIK3C2B expression
Breast cancer[35]	Tumor-suppressive	Transcriptional repressor of estrogen receptor α; inhibits receptor dimerization and DNA binding activity by interacting with its DNA-binding domain, suppressing estrogen-dependent cell proliferation
Breast cancer[46]	Pro-tumorigenic	In luminal B and HER2 subtypes, high mRNA expression is associated with worse relapse-free survival; ELF3 knockdown inhibits proliferation, colony formation, and anchorage-independent growth
Breast cancer[47,48]	Upregulated expression	Copy number gain at 1q32 is associated with ELF3 overexpression; among differentially expressed cancer driver genes in triple-negative breast cancer
Pancreatic cancer[49]	Pro-tumorigenic	Negatively regulated by miR-1224-5p; overexpression is associated with poor prognosis and advanced clinical stage; negatively correlated with immune cell infiltration
Pancreatic cancer[50]	Pro-metastatic	Netrin-1-ELF3 positive feedback loop promotes liver metastasis via hepatic stellate cell activation and retinoid signaling
Esophageal squamous cell carcinoma[51]	Downstream target	LINC00886 recruits SIRT7 to reduce H3K18 acetylation level at ELF3 promoter, inhibiting ELF3 expression; ELF3 promotes ZEB1/ZEB2 expression by binding miR-144 promoter, facilitating EMT
Esophageal small cell carcinoma[19]	Increased regulatory activity	ELF3 regulatory activity elevated in extracellular matrix fibroblasts (eCAFs)
Neuroendocrine carcinoma[52]	Pro-tumorigenic	One of super-enhancer-associated transcription factors; ELF3 knockdown leads to reduced cell viability
Prostate cancer[12]	Pro-tumorigenic	Overexpressed in primary and metastatic tumors; induced by IL-1β/NF-κB, interacts with NF-κB subunits p65/p50, enhancing their nuclear translocation and transcriptional activity

EMT: Epithelial-mesenchymal transition; ELF3: E74-like E26 transformation-specific transcription factor 3.

In stark contrast, another group of studies has revealed the tumor-suppressive functions of ELF3. In biliary tract cancer, Suzuki et al[32] reported that ELF3 directly inhibits ZEB2, maintains cell-cell junctions, and regulates CXCL16 to influence immune cell migration. In ovarian cancer, Yeung et al[33] confirmed that ELF3 overexpression inhibits cell proliferation and increases epithelial marker expression. In bladder urothelial carcinoma, Na et al[34] reported that the WNT7B/FZD5-ELF3-NOTCH1 signaling axis exerts tumor-suppressive effects. In breast cancer, Gajulapalli et al[35] reported that ELF3 acts as a transcriptional repressor of estrogen receptor α, inhibiting estrogen-dependent cell proliferation. Furthermore, in neuroendocrine carcinoma, ELF3 has been identified as a super-enhancer-associated transcription factor, with its knockdown leading to reduced cell viability and the downregulation of its target gene signature[36].

How can these cross-cancer functional differences be understood? The findings reported by Enfield et al[37] in lung adenocarcinoma provide important clues: ELF3 is a lineage-specifically amplified oncogene in lung adenocarcinoma, but this phenomenon was not observed in the lung squamous cell carcinoma of the same organ. This suggests that ELF3 function is closely correlated to the differentiation state of the cell of origin[38]. Upstream signaling inputs are equally important. In gastric cancer, Dong et al[39] reported that FZD5 signaling inhibits ZEB1 expression, and prevents EMT through the PKC-ELF3 axis, contrasting with the findings reported by Sun et al[21], and potentially reflecting the opposite regulation of ELF3 function under different upstream signaling contexts. The involvement of non-coding RNA networks further adds complexity. That is, ELF3-AS1 can promote gastric cancer progression[27], and form a negative feedback loop with SNAI2 to inhibit gastric cancer[40].

Based on the above analysis, the function of ELF3 does not exhibit strict consistency across gastric cancer and other tumors, but rather demonstrates significant context-dependence. In most epithelial-derived tumors, such as gastric cancer, colorectal cancer, and hepatocellular carcinoma, ELF3 predominantly exerts pro-tumorigenic effects, while in specific tumors, such as biliary tract cancer and ovarian cancer, it may play tumor-suppressive roles. For gastric cancer, the available evidence, including the functional mechanistic study conducted by Sun et al[21], the transcriptional network analysis conducted by Voutsadakis[25], and the non-coding RNA studies[26,27], collectively supports a pro-tumorigenic role for ELF3. Therefore, positioning ELF3 as a pro-tumorigenic factor in gastric cancer has a relatively robust evidence base. However, the contrasting findings reported by Dong et al[39] suggest that even in gastric cancer, ELF3 function may be subject to regulation by upstream signals. Future research needs to further elucidate whether ELF3 function remains consistent across different molecular subtypes or disease stages of gastric cancer. This represents both a challenge and an entry point for the deeper understanding of its biological essence (Table 1)[9-12,19,21,24-28,30-35,37,40-52].

THE DUAL MECHANISM OF ELF3 IN REGULATING CDH1 AND CXCL11 IN GASTRIC CANCER: DOES PRESENT EVIDENCE SUPPORT THIS MODEL?

Transcription factors participate in tumor progression by simultaneously regulating multiple downstream target genes to coordinate complex cellular behaviors. The proposed dual-action model of ELF3 in gastric cancer is illustrated in Figure 1. However, to what extent has this model been validated in gastric cancer?

The evidence currently comes from two types of findings. First, ChIP-seq has confirmed that ELF3 directly binds the CDH1 and CXCL11 promoters[21]. However, the physical binding itself does not equate to functional regulation. Is the outcome of binding activation or repression? Does binding indeed alter transcriptional output? These questions require other types of evidence to answer. Second, in gastric cancer tissues, ELF3 expression is negatively correlated with E-cadherin and CD8+ T cell infiltration[21]. These correlations provide indirect support for the ELF3 regulation of CDH1 and its involvement in immune modulation. However, correlation does not equal causation. The co-expression analysis at the tissue level cannot distinguish whether ELF3 inhibits CDH1 expression, whether cells with low CDH1 expression tend to have high ELF3 expression, whether ELF3 directly causes T cell exclusion, or whether ELF3-high expression tumors have other features that indirectly affect immune infiltration. These questions cannot be answered through correlational analysis alone.

The aforementioned binding evidence and expression correlations form the foundation of the model, but significant gaps remain at the functional validation level. First, the direction of transcriptional regulation has not been confirmed. Reporter gene assays can directly demonstrate whether ELF3 activates or inhibits CDH1 and CXCL11 transcription, but such studies have not been reported in gastric cancer. Second, changes at the protein level remain to be validated. Does E-cadherin protein increase upon ELF3 knockdown? Does CXCL11 secretion increase? These basic questions have not been directly answered in gastric cancer cells. Third, functional consequences remain unclear. Do changes in ELF3 expression actually affect gastric cancer cell invasion capacity? Do these affect T cell chemotactic migration? Transwell invasion assays and T cell chemotaxis experiments can answer these questions, but are similarly absent. Fourth, spatial evidence is lacking. In gastric cancer tissues in situ, do ELF3-high expression regions indeed show low E-cadherin expression and lack of CD8+ T cell infiltration? Multiplex immunohistochemistry can test this spatial association. Zhao et al[22] applied similar methods in a gastric cancer peritoneal metastasis research to reveal the spatial remodeling features of the TME. Furthermore, the single-cell transcriptomic analysis of esophageal small cell carcinoma revealed that ELF3 regulatory activity is elevated in extracellular matrix fibroblasts, suggesting the broader role for ELF3 in stromal cell reprogramming across gastrointestinal malignancies[53]. Finally, in vivo functional validation has not been conducted. Although establishing ELF3 knockout gastric cancer cell lines and observing the tumor growth, metastasis, and response to immunotherapy in humanized mouse models represents the gold standard for establishing in vivo ELF3 function, such studies remain absent in gastric cancer.

The appeal of the ELF3 dual-action model lies in its simplicity and explanatory power. A single molecule simultaneously connects intrinsic tumor cell properties and the extrinsic microenvironment, providing a unified framework for understanding gastric cancer progression. However, evidence currently supporting this model remains largely limited to binding evidence and correlations, with key links such as functional validation, spatial validation, and in vivo validation remaining absent.

This gap is not unique to gastric cancer. In a biliary tract cancer study, Suzuki et al[32] confirmed through functional experiments that ELF3 directly regulates multiple target genes, including ZEB2, CGN, ALOX5 and CXCL16, and revealed through conditioned medium experiments that ELF3 overexpression enhances NK cell and CD8+ T cell migration. These are precisely the types of functional validation missing in gastric cancer research (Table 1, including the biliary tract cancer findings). Similar experimental designs can readily be adapted to the gastric cancer field. Therefore, one of the priority directions for future gastric cancer ELF3 research is to fill the five evidence gaps identified above (from reporter gene assays to humanized mouse models), upgrading the “working hypothesis” to a “validated model”. This is both a challenge and an opportunity.

WHAT ARE THE CLINICAL TRANSLATIONAL PROSPECTS OF ELF3?

The ultimate value of any basic research lies on whether this can bring substantial improvement in clinical practice. For ELF3 in gastric cancer, its clinical translational potential is mainly reflected in two aspects: As a biomarker to guide patient stratification, and as a therapeutic target to intervene in disease progression. Both directions have led to progress, and both face challenges.

Evidence for ELF3 as a prognostic biomarker comes primarily from the analysis of clinical tissue samples. The immunohistochemical analysis conducted by Sun et al[21] in 100 STAD patients revealed that patients with high ELF3 expression had significantly shortened overall survival, with the multivariate analysis showing a hazard ratio exceeding 4.0. This effect size suggests that ELF3 immunohistochemistry may have clinical application value. Through the analysis of the TCGA database, Voutsadakis[25] also found that ELF3 mRNA expression levels are relatively high in gastric cancer, and correlate with the expression of other gastric cancer-related transcription factors[24,25]. An even more promising direction is ELF3 as a predictive biomarker for immunotherapy. Sun et al[21] reported that high ELF3 expression is negatively correlated with CD8+ T cell infiltration, linking ELF3 to the “cold” tumor phenotype. The theoretical basis is that high ELF3 expression may lead to CXCL11 inhibition, consequently impairing CTL recruitment via the CXCL9-11/CXCR3 axis, and forming an immune-excluded microenvironment[54].

Such tumors are unlikely to generate effective responses even when given immune checkpoint inhibitors. Therefore, ELF3 expression levels may help screen patients suitable for immunotherapy. Patients with a low expression may benefit from immunotherapy, while patients with a high expression may require interventions that reverse immune exclusion before immunotherapy. This hypothesis requires prospective validation in cohorts of gastric cancer patients receiving immunotherapy.

If ELF3 as a biomarker addresses the question “which patients need intervention”, ELF3 as a therapeutic target would address the question “how to intervene”. The latter faces more formidable challenges. The greatest obstacle to targeting ELF3 therapeutically is the long-standing perception of transcription factors as “undruggable”. However, research progress in other tumors provide referable paths for gastric cancer (Figure 2). Disrupting protein-protein interactions is presently the most mature strategy. The YK1 compound developed by Hwang et al[55], which disrupts the ELF3-MED23 interaction, can successfully inhibit the HER2 and KRAS expression, and restore cetuximab sensitivity in KRAS (G13D)-mutant colorectal cancer[11,55]. Similar strategies that target ETS factor interactions have been explored in structural studies[56]. This finding suggests that some HER2-positive gastric cancer patients with trastuzumab resistance may have abnormalities in ELF3-MED23 interactions, and can potentially benefit from YK1-class compounds. Pan-ETS inhibition is another path. YK-4-279 and its derivatives can simultaneously target multiple ETS family members, showing anti-tumor activity in melanoma and Ewing sarcoma[57-59]. Table 2 summarizes these representative agents and its key findings, providing referable paths and tool compounds for exploring ELF3-targeting strategies in the gastric cancer field. In gastric cancer, besides ELF3, ELK3 has been confirmed to participate in migration and invasion regulation[18,60], and pan-ETS inhibition might simultaneously block multiple pro-tumorigenic pathways. Targeting downstream effector molecules or upstream regulatory networks represents a more indirect strategy. Restoring the E-cadherin or CXCL11 expression can theoretically reverse EMT or enhance T cell recruitment. Intervening with non-coding RNAs, such as ELF3-AS1[27,40] or miR-320a-3p[42], can indirectly regulate the ELF3 expression. The involvement of ELF3 in non-coding RNA networks extends beyond gastric cancer. In breast cancer, the miR-320/ELF3 axis regulates tumor progression via the PI3K/AKT pathway, and similar regulatory mechanisms may be operative in gastric cancer[61]. However, these paths presently remain at the theoretical exploration stage, with their clinical application still distant.

Figure 2 Potential therapeutic strategies that target E74-like E26 transformation-specific transcription factor 3. A: Direct targeting strategies: Small molecule inhibitors (e.g., YK1) disrupt the E74-like E26 transformation-specific transcription factor 3 (ELF3)-MED23 interaction, inhibiting ELF3 transcriptional activity, with proof-of-concept established in colorectal cancer[11,55]; B: Indirect targeting strategies: Restoring the E-cadherin expression to reverse epithelial-mesenchymal transition, or restoring the CXCL11 expression to enhance cytotoxic T lymphocyte recruitment, presently at the theoretical exploration stage; C: Combination therapy approach: Combining ELF3-targeted agents with immune checkpoint inhibitors may produce synergistic effects in preclinical models. This figure is based on existing literature[11,59,64]. The above strategies await systematic evaluation in gastric cancer. The diagram is drawn by Figdraw (www.figdraw.com). EMT: Epithelial-mesenchymal transition; ELF3: E74-like E26 transformation-specific transcription factor 3.

Table 2 Therapeutic agents targeting E74-like E26 transformation-specific transcription factor 3 and related E26 transformation-specific transcription factors.

Agent	Target	Mechanism of action	Cancer type	Key finding
YK1 (compound 10)[11,55]	ELF3-MED23 interaction	Disrupts binding interface between ELF3 TAD domain and MED23 (amino acids 391-582), inhibits ELF3-MED23 protein-protein interaction, downregulates HER2 expression	Colorectal cancer (KRAS G13D), gastric cancer (HER2-positive)	Restores cetuximab sensitivity in colorectal cancer, inhibits EMT; significantly reduces HER2 levels and downstream signaling in HER2-positive gastric cancer cells, induces apoptosis and anti-proliferative effects; effective against both trastuzumab-sensitive and -resistant clones
YK-4-279[57-59]	Pan-ETS (EWS-FLI1, ETS1, PAX3-ETS, etc.)	Inhibits ETS factor transcriptional activity, interferes with interaction between ETS family members and PAX3, downregulates MET expression	Ewing sarcoma, melanoma, colon cancer	Inhibits cell growth, invasion, and ETS factor function in melanoma; induces hypersensitivity in p53-deficient BRAF V600E-mutant colon cancer, exerting effects through PARylation-mediated cell death (parthanatos)
(S)-YK-4-279[58]	EWS-FLI1	Optimized enantiomer of YK-4-279 with improved pharmacokinetic properties	Ewing sarcoma	Achieved sustained complete responses in 2 of 6 Ewing sarcoma rat xenograft models based on pharmacokinetic model-guided dosing
BRD32048[62]	ETV1	Directly binds ETV1, modulates ETV1-mediated transcriptional activity, inhibits p300-dependent acetylation, promotes ETV1 degradation	Prostate cancer	Inhibits ETV1-driven cancer cell invasion
EI-4[63]	ETS-1	Inhibits ETS-1 transcription factor activity (specific mechanism may involve inhibiting DNA binding)	Hepatocellular carcinoma	Inhibits hepatocellular carcinoma cell proliferation and invasion

EMT: Epithelial-mesenchymal transition; ETS: E26 transformation-specific; ELF3: E74-like E26 transformation-specific transcription factor 3.

From laboratory discovery to clinical application, this requires a clear translational path. For the biomarker direction, the prognostic value of ELF3 needs to be validated in larger, multicenter gastric cancer cohorts, in order to clarify its independence from traditional indicators, such as the tumor-node-metastasis stage and Lauren classification. Furthermore, its predictive value needs to be assessed in cohorts of patients who receive immunotherapy, in order to clarify its independence from PD-L1 CPS and MSI status. Moreover, technical issues, such as immunohistochemistry scoring standardization and optimal cut-off determination, need resolution. For the therapeutic target direction, the most realistic path at present is the systematic evaluation of existing compounds, such as YK1 and YK-4-279 (Table 2), in ELF3 high gastric cancer cell lines and humanized mouse models, particularly its combined application with immune checkpoint inhibitors. If preclinical models can demonstrate that ELF3 inhibition reverses immune exclusion and enhances immunotherapy sensitivity, this would provide a solid foundation for subsequent clinical trials.

The clinical translational prospects of ELF3 are clear, but practical application remains distant. As a biomarker, more clinical validation is needed. Furthermore, as a therapeutic target, more gastric cancer-specific research is required. These two directions are not mutually exclusive. If ELF3 is validated as a biomarker, patients with high ELF3 expression would naturally become the potential beneficiary population for targeted therapy. If targeting strategies achieve breakthroughs, this would reinforce the clinical value of ELF3 as a therapeutic target. Both point towards a common goal: Translating ELF3 research findings into tangible benefits for gastric cancer patients (Table 2)[11,55,57-59,62,63].

CONCLUSION

The growing body of evidence suggests that ELF3 may function as a context-dependent regulator with dual roles in gastric cancer progression, potentially linking tumor cell plasticity to immune evasion. However, significant gaps remain between present correlational findings and the functional validation required for clinical translation. High ELF3 expression identifies patients with poor prognosis and a “cold” tumor phenotype. However, its utility as a predictive biomarker for immunotherapy awaits prospective validation. As a therapeutic target, the preclinical success of compounds, such as YK1, in other cancers offers a referable strategy, but systematic evaluation in gastric cancer models is urgently needed. Moving forward, the field must prioritize in filling the validation gaps identified in the present review, from reporter assays to humanized mouse models, in order to determine whether targeting ELF3 can ultimately benefit gastric cancer patients.