Advances in epigenetic therapy for esophageal cancer.

Introduction
Esophageal cancer (EC) is a common malignancy worldwide, with a rising incidence and mortality rate that has garnered increasing global attention. According to the World Health Organization (WHO), approximately 600,000 new cases of esophageal cancer are diagnosed annually, with nearly half occurring in China, making it one of the most affected regions globally [1, 2]. In the United States, data from the American Cancer Society suggest a steadily increasing incidence, with an estimated 26,000 new cases expected in 2024 [3]. The development of esophageal cancer is associated with various risk factors, including prolonged exposure to irritants such as tobacco and alcohol, as well as chronic gastroesophageal reflux disease (GERD) [4–6]. Due to its insidious onset and rapid progression, most patients are diagnosed at an advanced stage, posing significant challenges for effective treatment [7].
Conventional treatments such as surgery, radiotherapy, and chemotherapy have achieved some improvement in patient outcomes; however, their effectiveness is still limited in advanced esophageal cancer. For early-stage esophageal cancer, surgical resection remains a relatively effective option, offering the potential for cure by removing the tumor and surrounding tissues. However, for advanced cases in which the cancer has spread to lymph nodes or distant organs, surgery is often not feasible or curative, and treatment tends to focus on palliative symptom relief rather than long-term survival [8–10]. Radiotherapy and chemotherapy are frequently employed in late-stage disease to alleviate symptoms, reduce tumor volume, and prolong survival [11, 12]. Nonetheless, these approaches have notable limitations. Radiotherapy may damage surrounding healthy tissues, leading to severe side effects such as esophageal stricture and dysphagia [13], while chemotherapy is often accompanied by the development of drug resistance, gradually diminishing its therapeutic efficacy [14].
Given these constraints, there is an urgent need for novel therapeutic strategies to improve survival rates and quality of life for patients with esophageal cancer. Against this backdrop, epigenetic therapy has emerged as a promising alternative, demonstrating considerable potential in preclinical and clinical studies. Epigenetic therapies modulate gene expression without changing the DNA sequence, thereby influencing critical cancer-related processes like proliferation, apoptosis, and metastasis [15]. This offers promising therapeutic options, particularly for patients with advanced disease.

Epigenetics and its role in cancer therapy
Epigenetics refers to heritable changes in gene expression and cellular phenotype that do not involve alterations in the underlying DNA sequence [16]. DNA methylation, histone modifications, and non-coding RNAs represent key regulatory mechanisms that dynamically and reversibly control gene activity [17]. DNA methylation, for instance, involves the covalent addition of methyl groups to cytosine residues, often resulting in transcriptional silencing [18]. Histone modifications, such as methylation, acetylation, and phosphorylation, reshape chromatin architecture and thereby influence transcriptional accessibility and gene expression [19, 20]. These epigenetic mechanisms are vital not only in normal physiological processes such as embryonic development and cell differentiation [21, 22], but also in the pathogenesis of a variety of diseases including cancer, cardiovascular disease, and neurodegenerative disorders [23–26].
Given their central role in gene regulation, epigenetic alterations have emerged as both key drivers of carcinogenesis and attractive targets for therapeutic intervention. In recent years, epigenetic therapy has become a rapidly evolving area in oncology [27]. One of the main therapeutic approaches is the use of epigenetic drugs (epidrugs), which are small molecules designed to modulate epigenetic regulators such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). These agents can reactivate silenced tumor suppressor genes and inhibit tumor cell proliferation [28–30]. For example, drugs targeting DNA methylation, such as 5-fluorouracil (5-FU) and cisplatin, have been widely used in cancer treatment [31]. Similarly, HDAC inhibitors (HDACis) and histone methyltransferase inhibitors (HMTis) have shown considerable promise in clinical and preclinical studies [32, 33].
Clinical evidence supports the efficacy and safety of several epidrugs in cancer treatment. FDA-approved HDAC inhibitors, including vorinostat and panobinostat, have demonstrated therapeutic benefits in specific lymphomas [34, 35]. Compared to traditional therapies, epigenetic approaches offer distinct advantages, such as improved selectivity and reduced toxicity [36, 37]. Moreover, combination strategies that integrate epidrugs with chemotherapeutic agents or immunotherapy have shown synergistic effects—enhancing tumor suppression, overcoming drug resistance, prolonging survival, and reducing adverse reactions [28, 38]. Because epigenetic drugs primarily act within tumor cells, they tend to spare normal tissues, thereby minimizing systemic side effects [27, 39]. These features underscore the growing significance of epigenetic therapy as a promising direction in cancer treatment, offering new hope for more targeted, effective, and personalized approaches.

Epigenetic alterations in esophageal cancer
Increasing evidence indicates that esophageal cancer is driven not only by genetic mutations but also by widespread and recurrent epigenetic alterations that reshape transcriptional programs. Here, we summarize the major categories of epigenetic dysregulation in esophageal cancer, including DNA methylation abnormalities, histone modification changes, and non-coding RNA deregulation.

DNA methylation abnormalities
DNA methylation represents one of the most extensively characterized epigenetic alterations in esophageal cancer and plays a central role in tumor initiation and progression. Under physiological conditions, the methylation status of CpG islands (CGIs) is tightly regulated by coordinated mechanisms involving transcriptional activity, DNA replication timing, chromatin context, and active demethylation, thereby maintaining genomic stability and proper gene expression [40]. During malignant transformation, this regulatory balance is disrupted, giving rise to two hallmark features: global hypomethylation and locus-specific promoter CGI hypermethylation [41].
Global DNA hypomethylation predominantly affects repetitive elements and transposable sequences, leading to chromosomal instability, aberrant recombination, and increased mutational burden [42]. In esophageal cancer, hypomethylation has been detected at precancerous stages and persists throughout disease progression, suggesting its involvement in early tumorigenesis [43]. A major consequence of this process is the reactivation of transposable elements such as LINE-1, whose aberrant mobilization can disrupt gene integrity, induce DNA damage, and reshape chromatin organization, thereby perturbing transcriptional regulatory networks [44, 45]. In parallel, oncogenes including COX-2 and c-Myc often exhibit hypomethylated promoter regions, resulting in transcriptional activation and contributing to enhanced tumor proliferation, invasion, and metastatic potential [46, 47].
In contrast, promoter CGI hypermethylation of tumor suppressor genes represents another defining feature of esophageal cancer. This alteration leads to stable transcriptional silencing and is widely regarded as an early and recurrent event during esophageal carcinogenesis [48]. Key regulators of cell cycle control and apoptosis, such as p16 and CDKN2A, are frequently inactivated through promoter hypermethylation, thereby facilitating uncontrolled proliferation, evasion of growth suppressors, and resistance to therapy [49–51]. Notably, recent studies have further revealed that aberrant hypermethylation of unmethylated regions (UMRs) in specific homeobox genes, including NKX2-5 and LHX1, may paradoxically activate oncogenic transcriptional programs, underscoring the context-dependent and multifaceted roles of DNA methylation in esophageal cancer [52].
Beyond its mechanistic importance, aberrant DNA methylation also holds substantial clinical relevance. Elevated methylation levels of specific gene panels have been correlated with advanced tumor stage and poor prognosis in esophageal cancer patients. Importantly, methylation signatures detected in circulating free DNA (cfDNA), such as composite panels including SEPT9, SHOX2, and RNF180, have demonstrated high sensitivity and specificity for esophageal cancer diagnosis [53]. These biomarkers further exhibit independent predictive value for postoperative recurrence and overall survival, highlighting their potential utility in noninvasive screening, prognostic stratification, and treatment monitoring.
Collectively, DNA methylation alterations in esophageal cancer follow a dual pattern of global hypomethylation and locus-specific hypermethylation, which cooperatively reshape the cancer epigenome and drive malignant transformation. The relative stability and tumor specificity of these changes render DNA methylation an attractive source of biomarkers and therapeutic targets, offering promising avenues for early detection, risk assessment, and precision oncology.

Histone modification dysregulation
Histone modifications constitute a central layer of epigenetic regulation in esophageal cancer, exerting profound effects on chromatin architecture, transcriptional programs, and cellular identity. By dynamically modulating nucleosome positioning and chromatin accessibility, histone modifications govern key malignant phenotypes, including uncontrolled proliferation, metastatic dissemination, therapeutic resistance, and immune evasion in esophageal squamous cell carcinoma (ESCC) [54, 55]. These regulatory processes are orchestrated by a highly coordinated system of epigenetic “writers,” “erasers,” and “readers,” whose dysregulation leads to widespread transcriptional reprogramming and tumor progression [56, 57].
Among histone modifications, acetylation represents one of the most extensively studied alterations in ESCC. Histone acetylation is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and disruption of this balance is frequently observed in tumor tissues. Global hypoacetylation of histones H3 and H4 has been reported in ESCC and is associated with aggressive phenotypes and poor clinical outcomes [58]. Functionally, this dysregulation is exemplified by the metastasis-associated protein MTA1, a core component of the nucleosome remodeling and deacetylase (NuRD) complex. Overexpression of MTA1 promotes histone H4 deacetylation, represses epithelial lineage genes, and facilitates epithelial–mesenchymal transition (EMT), thereby enhancing invasive and metastatic potential [59]. Conversely, oncogenic transcription factors can also exploit histone acetylation to sustain malignant transcriptional programs. For instance, SOX2 promotes global histone hyperacetylation through a dual mechanism: it transcriptionally activates multiple HATs while simultaneously suppressing long-chain acyl-CoA synthetase 5 (ACSL5), thereby redirecting acetyl-CoA from lipid biosynthesis toward nuclear histone acetylation [60].
More recently, histone lactylation has emerged as a novel modification linking tumor metabolism to epigenetic control. The enhanced aerobic glycolysis characteristic of ESCC leads to excessive intracellular lactate accumulation, which can serve as a direct substrate for histone lactylation. This modification provides a mechanism by which metabolic flux is translated into chromatin-based gene regulation [61, 62]. For example, lactylation of lysine 44 on the histone variant H2BC9 (H2BC9K44la) has been shown to activate Wnt/β-catenin signaling, thereby promoting tumor cell proliferation and shaping an immunosuppressive tumor microenvironment [63].
In addition to acetylation- and lactylation-based regulation, aberrant histone methylation also plays a critical role in ESCC pathogenesis. Tumor tissues frequently exhibit coordinated alterations in multiple histone marks, including increased H3K4 and H3K9 methylation together with reduced H3 and H4 acetylation. These combined epigenetic signatures correlate with advanced disease stage, poor differentiation, and unfavorable prognosis [58]. Importantly, histone-modifying enzymes may also exert noncanonical functions that extend beyond transcriptional regulation. For example, the H3K27me3 demethylase KDM6A contributes to genome stability through a catalytic-independent mechanism. By interacting with SND1, KDM6A facilitates the recruitment of DNA repair proteins such as RPA and Ku70 to stalled replication forks, thereby protecting nascent DNA strands and promoting replication fork stability. This function has been implicated in resistance to genotoxic chemotherapy, highlighting the multifaceted roles of histone regulators in cancer biology [64].
Collectively, aberrant histone modifications in ESCC reflect a highly interconnected regulatory network that integrates transcriptional control, metabolic adaptation, and genome maintenance. Rather than acting in isolation, these epigenetic layers cooperate to reshape chromatin states and sustain malignant phenotypes. Their reversibility and functional specificity make histone-modifying enzymes and associated regulatory complexes attractive candidates for biomarker development and therapeutic targeting in esophageal cancer.

Non-coding RNA dysregulation
In addition to DNA methylation and histone modifications, non-coding RNAs (ncRNAs) constitute a major regulatory layer of the cancer epigenome and play critical roles in the initiation, progression, therapeutic resistance, and clinical outcome of esophageal cancer. Rather than serving as passive transcriptional byproducts, ncRNAs actively orchestrate gene expression programs through diverse mechanisms, including post-transcriptional regulation, chromatin remodeling, and modulation of signaling pathways. Accumulating evidence indicates that dysregulated ncRNA networks contribute substantially to the malignant phenotypes of ESCC, highlighting their functional and clinical relevance.
MicroRNAs (miRNAs) are among the most extensively studied ncRNAs in esophageal cancer and primarily regulate gene expression by binding to complementary sequences in target mRNAs, leading to translational repression or mRNA degradation [65, 66]. Aberrant miRNA expression profiles have been consistently associated with tumor growth, invasion, epithelial–mesenchymal transition (EMT), and treatment resistance. For instance, oncogenic miRNAs such as miR-21 are frequently upregulated in ESCC and promote migration and invasion by suppressing tumor suppressor genes, whereas tumor-suppressive miRNAs, including miR-375, are often downregulated, thereby facilitating malignant progression. Beyond individual targets, miRNAs participate in complex regulatory circuits that fine-tune multiple signaling pathways simultaneously, reinforcing oncogenic transcriptional programs [67–70].
Long non-coding RNAs (lncRNAs) represent another major class of ncRNAs that regulate gene expression at epigenetic, transcriptional, and post-transcriptional levels [71]. In ESCC, numerous lncRNAs have been shown to modulate chromatin states by recruiting or interacting with DNA methyltransferases, histone-modifying enzymes (e.g., EZH2), and transcriptional regulators, thereby reshaping the epigenetic landscape [72]. In addition, many lncRNAs function as competing endogenous RNAs (ceRNAs), acting as molecular sponges that sequester miRNAs and release their target mRNAs from repression. LncRNAs such as HOTAIR are also overexpressed in esophageal cancer, modulating multiple targets including miRNAs and transcription factors to promote tumor aggressiveness [73].
Circular RNAs (circRNAs), once considered splicing artifacts, have recently emerged as important regulatory molecules in cancer biology [74]. In ESCC, circRNAs are deeply involved in regulating malignant phenotypes of tumor cells such as proliferation, apoptosis, invasion, metastasis, and drug resistance through multiple mechanisms, including acting as miRNA “sponges”, interacting with proteins, and even translating into functional polypeptides [75, 76]. Studies have found that the expression levels of multiple circRNAs are significantly correlated with the clinical stage, differentiation degree, lymph node metastasis, and prognosis of ESCC patients. For example, hsa_circ_0060927 is highly expressed in early ESCC tissues and can also serve as an auxiliary indicator for staging or prognostic evaluation [77].
Beyond these major subclasses, emerging evidence has also highlighted the oncogenic roles of small nucleolar RNAs (snoRNAs), which were traditionally thought to be restricted to ribosomal RNA modification [78]. Recent studies have revealed that snoRNAs can participate in tumor progression and therapy resistance. For example, SNORA58 has been shown to promote radioresistance in ESCC by modulating stress-response signaling pathways and ferroptosis-related processes, underscoring the expanding functional repertoire of ncRNAs in cancer [79].
Collectively, ncRNAs form a highly interconnected regulatory network that integrates post-transcriptional control with epigenetic remodeling and signal transduction. Through these coordinated actions, ncRNAs drive key malignant phenotypes, including sustained proliferation, EMT, metastasis, stemness, immune escape, and resistance to chemotherapy and radiotherapy. Importantly, the tissue specificity, stability, and detectability of ncRNAs in body fluids render them attractive candidates for noninvasive biomarkers and therapeutic targets. Continued characterization of ncRNA-mediated regulatory circuits is therefore expected to facilitate the development of more precise diagnostic tools and personalized therapeutic strategies for esophageal cancer.
These epigenetic changes provide valuable insights into the molecular mechanisms underlying esophageal cancer and offer promising avenues for diagnostic, prognostic, and therapeutic applications (Fig. 1).

Correlation between epigenetic alterations and clinical features in esophageal cancer
Emerging evidence indicates a strong association between epigenetic modifications and clinical characteristics of esophageal cancer. Aberrant DNA methylation patterns, particularly hypermethylation, correlate closely with tumor differentiation, lymph node metastasis, and depth of invasion, serving as indicators of poor prognosis [80–84]. Notably, the loss of 5-hydroxymethylcytosine (5-hmC), a product of ten-eleven translocation (TET) enzyme-mediated DNA demethylation, has been identified as an independent marker of unfavorable clinical outcomes in esophageal cancer patients [85]. In addition to DNA methylation, dysregulated histone modifications such as increased levels of histone H3 lysine 9 dimethylation (H3K9me2) and H3 lysine 27 trimethylation (H3K27me3) are associated with tumor stage and lymphatic metastasis, further underscoring their prognostic significance [86, 87].
MicroRNAs (miRNAs) have also demonstrated potential as diagnostic and prognostic biomarkers for esophageal cancer, with aberrant miRNA expression profiles reflecting tumor progression and therapeutic responsiveness [88]. Collectively, these epigenetic alterations provide valuable biomarkers for the prognosis assessment of esophageal cancer and offer promising targets for the development of personalized treatment strategies aimed at improving patient outcomes.

Advances in epigenetic therapeutic approaches for esophageal cancer

DNA methylation inhibitors
DNA methylation inhibitors, particularly those targeting DNA methyltransferases (DNMTs), have become a cornerstone of epigenetic therapy in esophageal cancer. These agents function primarily by inhibiting DNMT activity, thereby reducing aberrant DNA methylation and leading to the reactivation of tumor suppressor genes that were silenced during tumorigenesis. Decitabine (5-Aza-2′-deoxycytidine) is a representative DNMT inhibitor that not only enhances the expression of tumor-associated antigens such as MAGE-A3, thereby promoting T cell-mediated immune recognition, but also induces cell cycle arrest at the G2/M phase by restoring the expression of TGFBR2. These effects collectively suppress the proliferation and metastatic potential of ESCC cells [89, 90]. Additionally, other DNMT inhibitors including 5-azacitidine and RG108 have shown efficacy in sensitizing esophageal cancer cells to chemotherapy and radiotherapy by reversing epigenetic gene silencing, thus improving treatment responses [91, 92]. Overall, DNMT inhibitors represent a promising therapeutic approach, with potential applications in combination therapies tailored to individual patient profiles. Representative DNMT inhibitors and their mechanisms of action are summarized in Table 1.

Histone modification enzyme inhibitors and epigenetic readers
Inhibitors targeting histone modification enzymes constitute another vital class of epigenetic therapeutics for esophageal cancer. By modulating the activity of enzymes responsible for histone acetylation and methylation, these agents influence chromatin structure and regulate gene transcription. Among these, histone deacetylase inhibitors (HDACis) are one of the most extensively studied epigenetic drugs in esophageal cancer. Agents such as panobinostat have demonstrated significant anti-proliferative effects in ESCC cells, primarily through the induction of cell cycle arrest and apoptosis, partly via modulation of histone acetylation levels and upregulation of cell cycle inhibitors such as p21 [93]. In addition, HDAC inhibition has been shown to interfere with epithelial–mesenchymal transition (EMT), a key process underlying tumor invasion and metastasis. Notably, combination therapy involving the HDAC inhibitor vorinostat and the proteasome inhibitor bortezomib exhibits synergistic effects in suppressing EMT and enhancing anti-tumor efficacy [94], underscoring the therapeutic potential of combinatorial epigenetic strategies.
Beyond HDACis, histone acetyltransferase (HAT) inhibitors have also attracted attention as promising epigenetic modulators. Garcinol, a natural HAT inhibitor, suppresses tumor cell proliferation, invasion, and migration by targeting p300-mediated acetylation and modulating downstream signaling pathways such as TGF-β1 [95]. Furthermore, histone methyltransferase inhibitors further expand the repertoire of histone-targeting epigenetic agents. Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of the polycomb repressive complex 2 (PRC2), mediates trimethylation of histone H3 at lysine 27 (H3K27me3), a repressive chromatin mark associated with transcriptional silencing of tumor suppressor genes [96]. The EZH2 inhibitor Tazemetostat has been reported to disrupt oncogenic transcriptional networks, including c-Myc-driven signaling. This highlights the therapeutic potential of targeting histone methylation machinery. Importantly, combined inhibition of EZH2 and bromodomain and extra-terminal domain (BET) proteins has demonstrated enhanced antitumor efficacy in preclinical models [97], suggesting a synergistic therapeutic strategy. These findings underscore the growing complexity and promise of combinatorial epigenetic targeting in cancer therapy.
In recent years, increasing attention has been directed toward epigenetic “readers”, particularly the BET family of proteins, including BRD2, BRD3, and BRD4. These proteins recognize acetylated lysine residues on histone tails through their bromodomains and facilitate the recruitment of transcriptional machinery to active chromatin regions [98]. BET proteins play a critical role in sustaining oncogenic transcriptional programs, especially those driven by c-Myc and other super-enhancer–associated genes [99]. BET inhibitors, such as JQ1, competitively bind to bromodomains and displace BET proteins from chromatin, thereby suppressing transcription of key oncogenes. In esophageal cancer models, BET inhibition has been shown to attenuate tumor cell proliferation, induce apoptosis, and sensitize cancer cells to other therapeutic agents [100–102]. Table 2 provides an overview of selected histone-modifying enzyme inhibitors and their roles in esophageal cancer. Collectively, these histone modification enzyme inhibitors provide a diverse toolkit for epigenetic intervention in esophageal cancer, paving the way for improved therapeutic outcomes.

Regulation by non-coding RNAs
Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play pivotal roles in the epigenetic regulation of esophageal cancer. Antagonism of miR-455-3p has been shown to significantly enhance chemosensitivity and reduce the invasiveness of esophageal cancer cells [103]. The miR-99b/let-7e/miR-125a cluster contributes to tumor metastasis by promoting cell migration and invasion [104]. In addition, several other miRNAs, including miR-3656, miR-498, miR-32, miR-375, and miR-27b-3p, have been identified as potential diagnostic and prognostic biomarkers for esophageal cancer, highlighting their clinical relevance [70, 105–108].
Regarding lncRNAs, LINC00680 is highly expressed in esophageal cancer and correlates closely with tumor volume, stage, and prognosis. It promotes tumor proliferation by acting as a competing endogenous RNA (ceRNA) that sponges miR-423-5p, thereby regulating the expression of p21-activated kinase 6 (PAK6) [109]. VESTAR reduces VEGFC mRNA stability, inhibiting lymphangiogenesis and lymph node metastasis in ESCC [110]. LINC01554 facilitates metastasis by stabilizing tumor-associated transcripts such as HDGF via modulation of G3BP2; notably, the small molecule inhibitor C108 targeting G3BP2 significantly reduces cell metastasis, suggesting that LINC01554 inhibition may yield similar effects [111]. NORAD acts as a molecular sponge for miR-224-3p, upregulating MTDH and consequently decreasing esophageal cancer cell sensitivity to cisplatin [112]. Inhibition of AGPG leads to degradation of PFKFB3, suppressing glycolysis and cell proliferation [113]. Cancer-associated fibroblasts (CAFs) induce lncRNA DNM3OS expression through the PDGFβ/PDGFRβ/FOXO1 signaling axis, enhancing DNA damage repair and conferring radioresistance in ESCC [114]. The interferon-inducible lncRNA IRF1-AS forms a positive feedback loop with IRF1, promoting interferon signaling, inhibiting tumor progression, and serving as an independent prognostic marker [115].
These findings highlight the multifaceted functions of ncRNAs in esophageal cancer and their potential as diagnostic, prognostic, and therapeutic targets, providing new avenues for epigenetic-based personalized treatments. Table 3 summarizes selected ncRNAs with diagnostic and prognostic value in esophageal cancer.

Other mechanisms and therapies
Beyond the well-characterized epigenetic modifications driving esophageal cancer progression, emerging evidence highlights the pivotal roles of chromatin remodeling and nucleosome positioning as key epigenetic regulators in tumorigenesis. A large-scale analysis of 1,942 ESCC cases identified nine chromatin remodeling genes associated with increased cancer risk, among which the SWI/SNF complex (especially its homologous ATPase subunits SMARCA4 and SMARCA2) stands out as a critical regulator [116]. Notably, SMARCA2 is frequently mutated or epigenetically silenced in esophageal cancer, and synthetic lethality observed between SMARCA2 and SMARCA4 suggests the latter as a promising therapeutic target in SMARCA2-deficient tumors [117, 118]. These insights underscore chromatin remodeling’s fundamental role in esophageal cancer pathogenesis.
Nucleosome positioning, the spatial arrangement of nucleosomes along DNA, modulates transcription factor accessibility and thus gene expression. Studies reveal that nucleosome positioning stability correlates with germline mutation rates, though its direct involvement in esophageal cancer remains underexplored, representing a fertile ground for future epigenetic investigations [119].
In parallel, several natural bioactive compounds have surfaced as potent modulators of epigenetic landscapes in esophageal cancer. Resveratrol exerts multifaceted anticancer effects by modulating DNA methylation and histone acetylation, while enhancing the efficacy of HDAC and DNMT inhibitors [120]. Curcumin demonstrates anti-esophageal cancer activity by suppressing miR-21 expression, regulating apoptotic genes such as Pdcd4 and Bcl2, and potentiating gemcitabine-induced apoptosis [121, 122]. Epigallocatechin gallate (EGCG), a known histone modification agent, reactivates methylation-silenced genes through DNA methylation regulation, thereby inhibiting tumor growth [123, 124]. Collectively, these natural compounds offer promising avenues for developing novel epigenetic therapies. Deepening our understanding of their mechanisms and exploring synergistic combinations will be instrumental in advancing personalized epigenetic treatment strategies for esophageal cancer patients (Fig. 2).

Challenges and prospects
Epigenetic therapy, as a novel modality for esophageal cancer treatment, shows great potential but faces significant challenges. The dynamic and reversible nature of epigenetic modifications enables therapeutic intervention; however, post-treatment re-establishment of modifications like DNA methylation can lead to gene re-silencing, limiting long-term efficacy [125]. Moreover, the lack of drug specificity may induce off-target effects, activating normally silenced genes in healthy cells and increasing cancer risk. Delivery and stability issues, particularly the susceptibility of miRNAs to nuclease degradation in circulation, necessitate development of protective delivery systems. Additionally, determining optimal dosing is critical, as inappropriate doses may reduce therapeutic effect or harm patient health, posing barriers to clinical advancement.
In this context, emerging epigenome-wide and single-cell epigenomic technologies offer valuable opportunities to better understand the complexity and heterogeneity underlying epigenetic dysregulation in esophageal cancer. Genome-wide DNA methylation profiling has revealed pronounced inter- and intra-tumor epigenetic heterogeneity, which has been associated with tumor progression and unfavorable clinical outcomes [126, 127]. Meanwhile, single-cell epigenomic approaches, including assays for chromatin accessibility and histone modifications, enable high-resolution dissection of epigenetic states within heterogeneous tumor cell populations. These technologies facilitate the identification of rare or therapy-resistant subpopulations that are often obscured in bulk analyses, providing mechanistic insights into tumor evolution and treatment resistance [128, 129]. Although their application in esophageal cancer remains at an early stage, such high-resolution approaches are expected to play an increasingly important role in refining disease stratification and informing precision epigenetic therapies.
Despite these challenges, epigenetic therapy holds promising prospects. Advances in technology and research are expected to yield more precise and effective agents, such as selective inhibitors targeting DNA methyltransferases and histone-modifying enzymes, thereby minimizing damage to normal cells and reducing side effects. Therapies targeting miRNAs and long non-coding RNAs (lncRNAs) are also under development and may become essential components of esophageal cancer treatment. Personalized medicine will play a pivotal role, with treatment tailored according to patients’ genetic and epigenetic profiles to maximize efficacy. Combining epigenetic therapy with radiotherapy, chemotherapy, or immunotherapy is an emerging strategy, potentially enhancing tumor immunogenicity and overcoming resistance. Early clinical trials combining epigenetic agents with chemotherapy indicate improved survival and reduced toxicity [28].
In conclusion, as epigenetic understanding and technologies evolve, epigenetic therapy is poised to become an integral, personalized, and effective treatment approach for esophageal cancer, improving patient outcomes and quality of life.

Conclusion
Epigenetic therapy holds unprecedented promise in the treatment of esophageal cancer, providing novel avenues to tackle this challenging malignancy. Despite encouraging advances, significant obstacles remain. While several epigenetic drugs have entered clinical trials, the complexity of epigenetic regulation in cancer initiation and progression is not yet fully understood. Monotherapy with a single epigenetic agent often fails to produce substantial clinical benefits. Additionally, many current epigenetic drugs lack target specificity, and their side effects remain a concern. Given the multifactorial nature of esophageal cancer and notable inter-patient heterogeneity, personalized therapeutic strategies tailored to individual epigenetic and genetic profiles are essential.
Continued exploration of the epigenetic landscape in esophageal cancer will deepen our understanding of disease mechanisms and facilitate the identification of robust prognostic biomarkers. This, in turn, will enable the development of more precise and effective therapeutic approaches. With ongoing technological innovations and expanding research, epigenetic therapy is poised to become a cornerstone of personalized medicine for esophageal cancer, offering patients tailored, efficacious treatments and renewed hope in overcoming this formidable health challenge.