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Li JQ, Zhao HG, Cai HQ. Epigenetic-immune landscape of pancreatic ductal adenocarcinoma: From tumor biology to multimodal treatment in the surgical setting. World J Gastrointest Surg 2026; 18(11): 125757 [DOI: 10.4240/wjgs.125757]
Jun-Qi Li, Hong-Qiao Cai, Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
Hong-Guang Zhao, Department of General Surgery, Changchun Children’s Hospital, Changchun 130000, Jilin Province, China
Author contributions: Li JQ contributed to the discussion and design of the manuscript; Zhao HG contributed to the writing and editing of the manuscript, and review of the literature; Cai HQ designed the overall concept and outline of the manuscript; and all authors thoroughly reviewed and endorsed the final manuscript.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Hong-Qiao Cai, MD, PhD, Associate Professor, Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, Jilin Province, China. hongqiaocai@jlu.edu.cn
Received: July 16, 2026 Revised: August 14, 2026 Accepted: September 18, 2026 Published online: November 27, 2026 Processing time: 119 Days and 23.3 Hours
Abstract
Pancreatic cancer, one of the most lethal malignancies, is characterized by aggressive progression, late diagnosis, and resistance to conventional therapies. Increasing evidence indicates that epigenetic alterations contribute not only to tumor progression but also to immune regulation. These epigenetic alterations regulate immune cell differentiation, infiltration, and function, thereby promoting the formation of an immunosuppressive tumor microenvironment. This narrative minireview aims to summarize the current understanding of epigenetic-immune crosstalk in pancreatic ductal adenocarcinoma and discuss its potential implications for translational research and future therapeutic development. Various epigenetic-immune interactions regulate immune checkpoints, macrophages, myeloid-derived suppressor cells, and regulatory T cells, collectively contributing to immune evasion. Combinations of epigenetic modulators and immune checkpoint inhibitors are emerging, particularly in the surgical setting. They hold promise for restoring anti-tumor immunity and overcoming resistance. This article provides an overview of epigenetic-immune crosstalk in pancreatic cancer, with implications for novel therapies in the surgical setting. However, current evidence remains predominantly preclinical, and prospective studies are warranted.
Core Tip: This article highlights the important interplay between epigenetic alterations and the immune microenvironment. We summarize the roles of DNA methylation, histone modification, and non-coding RNAs in regulating immune checkpoints, macrophages, myeloid-derived suppressor cells, and regulatory T cells, all of which contribute to an immunosuppressive tumor microenvironment. We also discuss therapies combining epigenetic modulators with immune checkpoint inhibitors in the surgical setting. Furthermore, we explore advances in multi-omics technologies that deepen our understanding of epigenetic-immune crosstalk. Ultimately, we emphasize targeting the epigenetic-immune axis as a strategy to enhance anti-tumor immunity and improve patient outcomes.
Citation: Li JQ, Zhao HG, Cai HQ. Epigenetic-immune landscape of pancreatic ductal adenocarcinoma: From tumor biology to multimodal treatment in the surgical setting. World J Gastrointest Surg 2026; 18(11): 125757
Pancreatic cancer is among the most lethal malignancies, and pancreatic ductal adenocarcinoma (PDAC) represents its most common histological subtype. Despite advances in surgical techniques, systemic therapy, and perioperative management, the prognosis of PDAC remains poor[1], largely due to its aggressive nature, late diagnosis, and resistance to conventional therapies[2]. Over the past decade, progress has been made in understanding the pancreatic cancer tumor microenvironment (TME)[3]. Epigenetic alterations and immune cells are both critical in shaping the PDAC TME[4]. Herein, we aim to discuss epigenetic reprogramming, its influence on immune responses, and its role in creating an immunosuppressive TME (Figure 1). We also explore the most recent therapies involving epigenetic regulators and immune checkpoints in the surgical setting. Our goal is to provide a clinically oriented framework for understanding how epigenetic-immune interactions may inform future therapeutic strategies in the surgical management of PDAC. Although previous reviews have summarized epigenetic alterations or immune dysregulation in PDAC separately, few have systematically integrated these two dimensions within the specific context of surgical oncology. This distinction is clinically important because surgery remains the only potentially curative treatment for PDAC. However, recurrence after resection is common and is strongly influenced by residual tumor cells, immune escape, stromal remodeling, and therapy-resistant tumor phenotypes. Therefore, the perioperative period represents a unique therapeutic window in which epigenetic modulation may reshape tumor immunogenicity, enhance antigen presentation, increase T-cell infiltration, and improve responsiveness to immune-based or multimodal treatment strategies. By focusing on the intersection between epigenetic regulation, immune microenvironment remodeling, and surgical treatment, this review aims to provide a more clinically oriented framework for understanding how epigenetic-immune crosstalk may inform neoadjuvant therapy, postoperative recurrence prevention, biomarker-guided patient selection, and future translational strategies in PDAC.
Figure 1 Epigenetic reprogramming and immune microenvironment crosstalk in pancreatic ductal adenocarcinoma.
Major epigenetic alterations, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, interact with immune components in the pancreatic tumor microenvironment. These epigenetic events may regulate chemokine expression, antigen presentation, immune checkpoint activity, macrophage polarization, myeloid-derived suppressor cell recruitment, Treg accumulation, and cytotoxic T-cell dysfunction. PD-L1: Programmed death-ligand 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; CXCL9/CXCL10: C-X-C motif chemokine ligand 9/10; CCL2: C-C motif chemokine ligand 2; IL-10: Interleukin-10; TAM: Tumor-associated macrophage; MDSC: Myeloid-derived suppressor cell; Treg: Regulatory T cell; NK: Natural killer.
LITERATURE SEARCH AND SELECTION APPROACH
This narrative review was conducted through a comprehensive literature search of PubMed/MEDLINE, Web of Science, and ClinicalTrials.gov. The search strategy combined the following terms: “Pancreatic ductal adenocarcinoma”, “epigenetic regulation”, “DNA methylation”, “histone modification”, “non-coding RNA”, “chromatin remodeling”, “tumor immune microenvironment”, “immune checkpoint inhibitor”, “immunotherapy”, and “neoadjuvant therapy”. Articles published up to July 2026 were considered. Studies were selected based on their relevance to epigenetic-immune interactions in PDAC and their contribution to mechanistic understanding, translational development, or clinical application. Priority was given to original research articles, clinical trials, and high-quality reviews. As this article is a narrative review, no formal meta-analysis or systematic risk-of-bias assessment was performed.
THE TME IN PDAC
The pancreatic cancer TME is characterized by dense stroma, which contains extracellular matrix, fibroblasts, immune cells, and blood vessels[5]. These components are unique and support a hostile environment for tumor growth, invasion, and metastasis[6]. Immune cells, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), are important for the microenvironment. They promote immune evasion and therapeutic resistance[7]. However, the immune infiltration and TME suppression are incompletely understood[8]. Recent research has pointed to epigenetic alterations as a key driver in modulating immune cell behavior and orchestrating the immunosuppressive TME in PDAC, as shown in Table 1.
Table 1 Epigenetic alterations in pancreatic ductal adenocarcinoma.
Epigenetic alteration
Modulators
Mechanisms
Therapeutic relevance
Overall impact on tumor progression
DNA methylation
5-azacytidine, EZH2 inhibitor
Hypermethylation of tumor suppressor genes; hypomethylation of oncogenes; modulation of chemokines
Epigenetic drugs can sensitize tumors to immunotherapy
Inhibits immune evasion; Downregulates tumor progression when combined with immunotherapy
Histone modifications
HDACs, H3K4me3, other histone marks
Alteration of chromatin accessibility and gene expression; repression of immune-related genes
HDAC inhibitors may restore anti-tumor immunity and enhance checkpoint blockade therapy
Promotes immune suppression if unmodulated; inhibition restores immune surveillance
Epigenetic modifications include DNA methylation, histone modifications, and non-coding RNAs, which are known to regulate gene expression without altering the underlying DNA sequence[8]. These alterations have profound effects on cancer progression by modifying the expression of genes involved in cell proliferation, apoptosis, and immune responses[9]. In PDAC, several key epigenetic alterations have been identified that modulate immune cell infiltration and function.
DNA methylation
Abnormal DNA methylation patterns are commonly observed in PDAC[10]. Hypermethylation of tumor suppressor genes and hypomethylation of oncogenes contribute to tumorigenesis. This can occur through silencing of critical immune response genes or enhancement of immune evasion mechanisms[10]. Li et al[11] found upregulation of Th1 chemokines such as C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10, along with increased cytotoxic T cell infiltration, in mouse pancreatic tumors. This occurred when the epigenetic drugs 5-azacytidine (a DNA methylation inhibitor) and an EZH2 inhibitor (a histone methylation inhibitor) were combined with anti-programmed cell death ligand 1 (PD-L1) therapy, demonstrating that epigenetic therapy can overcome the suppressed immune microenvironment in PDAC[11].
Histone modifications
Histone modifications include acetylation, methylation, and phosphorylation, and they regulate chromatin structure and gene accessibility[12]. Abnormal histone modifications in PDAC influence the expression of genes involved in immune activation[13]. One study integrated histone modification data with gene expression profiles and identified distinct epigenetically regulated protein-coding genes that correlated with differences in chemokine expression, immune checkpoint genes, and TME cell abundance[14]. HDACs repress immune gene expression, resulting in an immunosuppressive TME[15]. In a preclinical PDAC model, C57BL/6 mice were implanted with Panc02 cells and treated with the pan-HDAC inhibitor vorinostat (50 mg/kg/day) for 14 days[16]. CD8+ T cell infiltration was significantly increased in the tumors. Peng et al[17] reported that HDAC inhibition increased major histocompatibility complex (MHC) class I expression and T cell infiltration in PDAC models. This study demonstrated a link between histone modification and immune stimulation[17].
Non-coding RNAs
MicroRNAs (miRNAs) and long non-coding RNAs are key regulators of gene expression at the post-transcriptional level[18]. In PDAC, dysregulated miRNAs can influence immune responses by targeting immune-related genes[19]. miRNAs that suppress the expression of tumor suppressors or immune-stimulatory cytokines can promote immune evasion and tumor progression[20]. Among non-coding RNAs, miR-301a has been shown to promote M2 macrophage polarization in PDAC. In vitro co-culture of Panc1 cells overexpressing miR-301a with Tohoku Hospital Pediatrics-1 (THP-1)-derived macrophages increased M2 markers (CD206+) by 2.3-fold, whereas miR-301a knockdown reversed this effect. Mechanistically, miR-301a targets phosphatase and tensin homolog, activating the phosphoinositide 3-kinase gamma (PI3Kγ) pathway to drive immunosuppressive macrophage polarization[21]. PDAC cells also overexpress miR-203, miR-146a, and miR-212-3p to downregulate dendritic cell (DC) costimulatory markers such as CD80, CD86, and MHC II, thereby reducing antigen presentation and enabling immune escape. Downregulation of miR-4299 and miR-153 decreases activating ligands for natural killer (NK) cells, such as NKG2D ligands, dampening NK cell activity.
Emerging evidence indicates that the dysregulated expression of miRNAs and long non-coding RNAs in PDAC is often driven by upstream epigenetic alterations, establishing an “epigenetic-non-coding RNA-immune” regulatory axis. Long non-coding RNAs also play a role in modulating immune responses, particularly in the regulation of immune cell polarization and differentiation[22,23]. For example, PSMB8-AS1 sponges miR-382-3p, thereby increasing signal transducer and activator of transcription 1 and PD-L1 and promoting immune evasion. LINC00473 sponges miR-195-5p, resulting in PD-L1 upregulation and reduced T cell activation[24]. By linking DNA modifications to non-coding RNA expression and downstream immune effects, this framework provides a cohesive mechanistic view of how epigenetic reprogramming orchestrates immunosuppression in the pancreatic TME.
Chromatin remodeling
Chromatin remodeling is fundamental to epigenetic regulation. It controls gene accessibility and transcription through multiple nucleosome repositioning events. In PDAC, chromatin remodelers are important for both tumor cells and the immune microenvironment. Several key chromatin remodeling complexes have been identified, including switch/sucrose non-fermentable, imitation switch (ISWI), chromodomain helicase DNA-binding (CHD), and inositol 80 (INO80)[25]. These complexes modulate chromatin structure at promoters and enhancers and are involved in proliferation, apoptosis, and immune regulation. ARID1A and SMARCA4 are frequently mutated in PDAC, leading to altered nucleosome positioning and transcriptional dysfunction[26,27]. The ISWI and CHD families affect chromatin at enhancers[28]. Immune checkpoint genes such as PD-L1, as well as genes encoding cytokines such as transforming growth factor beta (TGF-β) and interleukin (IL)-10, are indirectly regulated, thereby influencing T cell and macrophage polarization. INO80 complexes accelerate DNA repair and replication[28]. However, their dysfunction also affects enhancer-promoter looping of immunomodulatory genes. As a result, DC activation and NK recognition are impacted.
Taken together, these epigenetic mechanisms should not be viewed as independent molecular abnormalities. They are interconnected regulatory layers that converge on distinct immune phenotypes in PDAC. Aberrant DNA methylation may silence immune-stimulatory genes and alter chemokine expression. Aberrant DNA methylation may limit cytotoxic T-cell recruitment and contribute to a “cold” tumor phenotype. Histone modifications can further regulate chromatin accessibility at antigen-presentation genes, immune checkpoint loci, and cytokine-related genes. Histone modifications may influence MHC-I expression, PD-L1 activity, and T-cell infiltration. Dysregulated non-coding RNAs provide an additional post-transcriptional layer by promoting M2 macrophage polarization, suppressing DC co-stimulatory molecules, impairing NK-cell activation, and enhancing PD-L1-mediated immune evasion. Chromatin remodeling abnormalities may reinforce these effects by reshaping enhancer and promoter accessibility of immunomodulatory genes. Therefore, the epigenetic landscape of PDAC contributes to a coordinated immunosuppressive state. This state is characterized by reduced antigen presentation, T-cell dysfunction, macrophage- and MDSC-mediated suppression, Treg enrichment, and impaired response to immune checkpoint blockade. Clinically, this framework helps explain why epigenetic reprogramming may influence neoadjuvant treatment response, postoperative residual disease, recurrence risk, and the selection of patients for epigenetic-immunotherapy combinations in the surgical setting.
EPIGENETIC-IMMUNE CROSSTALK IN PDAC
There are two directions of crosstalk between epigenetic alterations and the immune microenvironment. Epigenetics can alter immune behavior, and immune activity can, in turn, affect tumor epigenetics. This bidirectional crosstalk is vital in the development of the immunosuppressive TME, promoting immune evasion and therapy resistance. Several key mechanisms by which epigenetic modifications contribute to immune suppression in PDAC are listed in Table 2.
Table 2 Immune-epigenetic crosstalk in pancreatic ductal adenocarcinoma.
Immune component
Epigenetic alterations
Molecular targets
Effect
Function
Immune checkpoint regulation
DNA hypomethylation; reduced H3K9me3/H3K27me3; H3K4me3 deposition
PD-1, PD-L1, CTLA-4; KMT2 family-mediated H3K4me3 at PD-L1 promoter
Increased expression of PD-1, PD-L1, and CTLA-4; inhibition and exhaustion of T cells
Promotes immune evasion, reduces anti-tumor T-cell activity, contributes to resistance to checkpoint therapy
TAMs
Histone modifications; H3K4me3
Opn promoter and other immunosuppressive genes
Promotes M2 polarization of macrophages; increases secretion of TGF-β and IL-10; enhances recruitment to the tumor
Strengthens immunosuppressive tumor microenvironment, supports tumor growth and immune evasion
Epigenetic alterations directly modulate the expression of immune checkpoint genes, such as programmed cell death protein 1 (PD-1), PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which are crucial for restraining T cell activity. Abnormal DNA methylation and histone modifications of immune checkpoint genes result in their high expression, leading to immune exhaustion and immune evasion. Specifically, the histone methyltransferase lysine methyltransferase 2 mediates H3K4me3 deposition at the PD-L1 promoter, increasing its expression and promoting T-cell inhibition in PDAC[29]. Epigenetic inhibitors targeting this enzyme may improve the efficacy of anti-PD-1 therapy in mice. Genome-wide analysis has revealed DNA hypomethylation and reduced repressive histone marks such as H3K9me3 and H3K27me3, leading to increased expression of PD-1, CTLA-4, and other immune checkpoint genes under epigenetic control[30].
TAMs and myeloid cells
TAMs and MDSCs are important mediators of immune suppression, and epigenetic reprogramming drives their immunosuppressive functions. Secretion of pro-inflammatory cytokines and growth factors enhances tumor growth and immune evasion. Histone modifications in MDSCs increase their recruitment to tumors and the secretion of immunosuppressive molecules including TGF-β and IL-10. H3K4 trimethylation is increased at the osteopontin (Opn) promoter, which increases Opn expression and strengthens MDSC immunosuppressive activity[31]. Inhibition of WD repeat-containing protein 5 inhibition reduces MDSC immunosuppression and improves anti-PD-1 immunotherapy in mice.
Tregs
Tregs play a critical role in TME suppression. Epigenetic modifications enhance tumor-associated Tregs, leading to immune suppression. DNA methylation and histone deacetylation are important in regulating Tregs in pancreatic cancer. Abnormal epigenetic mechanisms increase immune checkpoints and immunosuppressive cell populations such as Tregs, MDSCs, and TAMs. Immune resistance and T cell dysfunction may be associated with these changes[25].
From a therapeutic perspective, the epigenetic regulation of immune components in PDAC provides several actionable opportunities. TAMs are frequently skewed toward an M2-like immunosuppressive phenotype. Epigenetic modulation may help redirect macrophage polarization toward a more pro-inflammatory and tumoricidal state. Similarly, MDSCs maintain immune suppression through histone modification-dependent transcriptional programs. These programs may enhance the production of suppressive mediators such as TGF-β and IL-10. Targeting these programs may reduce MDSC recruitment and restore T-cell cytotoxicity. Tregs represent another clinically relevant immune population. Epigenetic mechanisms contribute to Treg accumulation and suppressive function within the TME. Therefore, combining epigenetic modulators with immune checkpoint inhibitors, vaccines, adoptive cell therapy, or neoadjuvant multimodal treatment may improve antitumor immunity by simultaneously targeting tumor-cell-intrinsic immune evasion and immune-cell-mediated suppression. This immune-cell-specific framework may also support biomarker-guided therapeutic stratification in the surgical setting, particularly for patients at high risk of residual disease or postoperative recurrence.
EMERGING THERAPEUTIC STRATEGIES IN THE SURGICAL SETTING
Epigenetic modulators combined with immune checkpoint inhibitors
Given that epigenetic alterations modulate the PDAC immune microenvironment, focusing on epigenetic regulators and immune checkpoint inhibitors is promising[32]. DNA methyltransferase inhibitors, HDAC inhibitors, and histone acetyltransferase inhibitors reverse epigenetic silencing and restore TME immune function[33]. Preclinical studies have shown that the combination of epigenetic modulators with immune checkpoint inhibitors can enhance antitumor immunity and improve therapeutic outcomes, especially in the surgical setting[34]. Immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, have shown promise in other cancers but have limited efficacy in pancreatic cancer[35]. Several recent studies provide concrete evidence for the opportunities and limitations of combining epigenetic modulators with immune checkpoint blockade in PDAC. In a phase II study of entinostat plus nivolumab in advanced PDAC, entinostat was administered as a 14-day lead-in followed by combination therapy with nivolumab[36]. Among 27 evaluable patients, three achieved partial responses, corresponding to an objective response rate of 11%, with a median response duration of 10.2 months. However, the median progression-free survival and overall survival were 1.89 months and 2.73 months, respectively. The primary endpoint was not met. Importantly, exploratory immune profiling showed increased DC activation and enrichment of inflammatory response pathways. Thus, HDAC inhibition may induce measurable immune remodeling even when clinical benefit is limited to a subset of patients. A second phase II study evaluated azacitidine plus pembrolizumab in previously treated locally advanced or metastatic PDAC[37]. This regimen was generally tolerable, but its antitumor activity was modest. Among 31 patients evaluable for efficacy, three achieved partial responses, and the disease control rate was 35.5%. The median progression-free and overall survival were 1.51 months and 4.83 months, respectively. Notably, exploratory biomarker analysis suggested that higher baseline CD8+ T-cell infiltration and lower Ki-67 expression may be associated with more favorable responses. However, PD-L1 and CD68 expression alone were not predictive. These findings suggest that epigenetic priming plus PD-1 blockade may require biomarker-guided patient selection rather than broad application to unselected PDAC populations. In addition, the phase Ib study NCT03257761 of guadecitabine plus durvalumab is evaluating a DNA methyltransferase inhibitor combined with PD-L1 blockade in patients with advanced liver, pancreatic, bile duct, or gallbladder cancers. This study is designed to assess safety, dose-limiting toxicities, objective response, progression-free survival, and overall survival. Its translational endpoints include PD-1/PD-L1 expression, effector T cell/Treg ratio, circulating MDSC levels, inflammatory T-cell signatures, tumor neoepitope-specific T-cell responses, and methylation-related changes. Although mature PDAC-specific efficacy results remain limited, this trial illustrates how future epigenetic-immunotherapy studies can integrate clinical endpoints with immune and epigenetic biomarkers. Overall, these studies indicate that epigenetic-immunotherapy combinations are mechanistically plausible and clinically feasible, but current clinical benefits remain restricted to selected patient subsets.
Immune cell-targeted epigenetic reprogramming
Recent studies suggest that combining these therapies with epigenetic modulators may overcome immune resistance, because they can reprogram the TME and enhance immune cell activity[38]. For example, inhibitors of DNA methylation or HDACs can increase the expression of PD-L1 on tumor cells, enhancing the effectiveness of immune checkpoint blockade[39,40]. In addition to targeting tumor cells directly, strategies to reprogram immune cells within the TME are also under investigation[41]. For example, modulating the epigenetic status of TAMs, MDSCs, and Tregs to reduce their immunosuppressive functions can improve the efficacy of immunotherapies[42]. DC epigenetic modulation increases T cell activation and tumor immune response. Epigenetic modulators can be combined with checkpoint inhibitors, adoptive cell therapy, and vaccines. By targeting immunosuppressive cells (TAMs, MDSCs, and Tregs), the TME can be reshaped[43]. The temporal dynamics of epigenetic remodeling and immune crosstalk are important. Studying how epigenetics change during tumor progression and therapy may bring adaptive treatment strategies against immune evasion.
Neoadjuvant epigenetic-immunotherapy strategies to improve surgical outcomes
The surgical setting may represent a potential therapeutic window for investigating epigenetic-immune strategies, although direct clinical evidence remains limited[44]. Surgical resection remains the only potentially curative treatment for PDAC. However, many patients experience early recurrence[45]. Preclinical evidence suggests that neoadjuvant epigenetic-immune strategies may enhance tumor immunogenicity[46]. However, their ability to improve surgical outcomes requires prospective validation. Moreover, they can reduce immune escape and improve complete tumor eradication. Epigenetic therapies can induce a more immune-responsive tumor phenotype by restoring the expression of tumor-associated antigens, antigen-presenting molecules, and interferon-related signaling pathways. Epigenetic and DNA-repair vulnerabilities represent potential therapeutic opportunities in PDAC. While DNA methyltransferase inhibitors and histone deacetylase inhibitors may enhance immune responsiveness, other molecular strategies such as methyltransferase-like 16 (METTL16) targeting may increase sensitivity to DNA-damage-based therapies, including poly(ADP-ribose) polymerase inhibition[47,48].
Epigenetic regulation in postoperative residual disease and recurrence prevention
The persistence of minimal residual disease is strongly influenced by epigenetic plasticity. Epigenetic vulnerabilities associated with residual disease represent a potential area for recurrence-prevention research[49]. Epigenetic modulators may reverse abnormal DNA methylation patterns, restore tumor suppressor gene expression, and enhance immune-mediated elimination[50]. Emerging evidence suggests that circulating tumor DNA and molecular biomarkers may assist postoperative recurrence monitoring and risk stratification[51]. All of these can guide postoperative treatment decisions.
Integration of artificial intelligence and translational models in surgical epigenetic therapy
Artificial intelligence, patient-derived organoids, and humanized mouse models may bring new clinical insights[52]. Artificial intelligence-based algorithms can integrate multi-omics datasets[53], using DNA methylation profiles, histone modification patterns, transcriptomic signatures, and immune landscapes to identify therapeutic targets in surgical patients. Patient-derived organoids provide a valuable tool for evaluating epigenetic-immunotherapy combinations in a personalized manner[54,55]. In addition, humanized mouse models allow for investigation within a human-relevant environment.
CHALLENGES AND FUTURE DIRECTIONS
Despite the aforementioned advances, challenges that hinder clinical translation into effective therapies remain.
Tumor heterogeneity
PDAC heterogeneity poses a major challenge[56]. Individuals differ in epigenetic modifications, immune infiltration, and stromal composition, making it difficult to predict response rates[57]. The TME is complex, with dense stroma and immunosuppressive cells[58]. These factors all limit drug efficacy, particularly for immune checkpoint antibodies. The optimal timing, dose, and sequence of epigenetic therapy combined with immunotherapy remain unconfirmed.
Clinical translation
Despite the synergistic effects of combining DNA methyltransferase inhibitors, histone deacetylase inhibitors, and other epigenetic modulators with checkpoint blockade, clinical translation still requires optimization between efficacy and toxicity[36]. Several clinical studies have explored combining epigenetic therapies with immune checkpoint inhibitors in pancreatic cancer. DNA methylation inhibitors are also being evaluated. Clinical trials of azacitidine plus pembrolizumab (phase II, NCT03264404) and guadecitabine plus durvalumab (phase I, NCT03257761) are ongoing[37]. They aim to investigate whether epigenetic reprogramming sensitizes tumors to checkpoint blockade. Recent clinical and translational studies have refined our understanding of immuno-epigenetic therapy in PDAC. The phase II study of entinostat plus nivolumab demonstrated that HDAC inhibition combined with PD-1 blockade can induce measurable immune remodeling in some patients, but the overall clinical benefit remained limited, with responses restricted to a small subset. Similarly, the phase II study of azacitidine plus pembrolizumab showed manageable safety but modest antitumor activity, suggesting that DNA methylation inhibition plus immune checkpoint blockade may require biomarker-guided patient selection. These studies indicate that epigenetic priming is biologically plausible but insufficient as a universal strategy for all patients with PDAC. Recent mechanistic studies further suggest that epigenetic or metabolic-epigenetic regulation may influence macrophage polarization, antigen presentation, MHC-I expression, T-cell infiltration, and resistance to immune checkpoint blockade. Therefore, future immuno-epigenetic strategies should move beyond empirical drug combinations and focus on rational sequencing, immune and epigenetic biomarker stratification, and integration with neoadjuvant or perioperative treatment strategies.
Off-target effects and toxicity
Epigenetic drugs may lead to off-target effects and immune-related adverse events. 5-Azacytidine or decitabine usually cause myelosuppression and thrombocytopenia. Vorinostat induces gastrointestinal reactions (nausea, diarrhea) and occasional immune-mediated adverse events[59]. These toxicities limit dosing and combination therapy. To address this, intermittent or low-dose schedules, careful sequencing, and close monitoring should be considered.
Biomarker limitations
Biomarkers for patient stratification remain limited[60]. Identifying predictive biomarkers is critical[61]. They should reflect epigenetic status, immune status, and therapy response for clinical trials. DNA methylation, histone modification, or non-coding RNA signatures may predict immunosuppressive states and guide personalized therapies. Dynamic monitoring during treatment may provide real-time insights into therapeutic response[62]. Single-cell and spatial multi-omics technologies may identify novel epigenetic and immunological targets[63].
CONCLUSION
PDAC is lethal, characterized by aggressiveness, late diagnosis, and therapy resistance. Epigenetic alterations, including DNA methylation, histone modifications, and non-coding RNAs, shape the immune microenvironment by regulating checkpoints, macrophages, MDSCs, and Tregs. They also create an immunosuppressive TME. Combining epigenetic modulators with immune checkpoint inhibitors is promising for restoring anti-tumor immunity and enhancing T-cell responses. Single-cell and spatial multi-omics provide insights into epigenetic-immune crosstalk, enabling personalization. Tumor heterogeneity, limited biomarkers, and off-target effects remain challenging. Targeting epigenetic-immune crosstalk to convert “cold” tumor into “hot” tumor holds promise for better outcomes in the surgical setting. Overall, recent evidence supports the concept that epigenetic regulation and immune remodeling are closely interconnected in PDAC. However, the clinical translation of immuno-epigenetic therapy remains at an early stage. Current trials demonstrate feasibility but also highlight limited efficacy in unselected populations. A key challenge for future studies is to identify which patients are most likely to benefit, when epigenetic modulation should be delivered, and how these agents should be combined with immune checkpoint inhibitors, chemotherapy, radiotherapy, vaccines, or adoptive cell therapies. In the surgical setting, these questions are particularly important because neoadjuvant therapy, residual disease control, and recurrence prevention provide clinically meaningful windows for intervention.
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