Epigenetic-immune landscape of pancreatic ductal adenocarcinoma: From tumor biology to multimodal treatment in the surgical setting

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
miRNAs	miR301a, miR340, miR203, miR146a, miR2123p, miR4299, miR153	Target immune-related genes	miRNA modulators could reprogram TME or enhance immunotherapy	Promotes immune evasion and tumor progression
lncRNAs	PSMB8AS1, LINC00473	Function as “miRNA sponges”, derepressing targets like STAT1 and PDL1	Targeting lncRNAs or their miRNA axes could downregulate PD-L1-mediated immunosuppression	Promotes immune evasion and tumor progression
Chromatin remodeling	SWI/SNF, ISWI, CHD, INO80	Repositions nucleosomes; regulates enhancer or promoter accessibility	Modulation of remodelers may restore immune-stimulatory gene expression and improve immunotherapy response	Promotes immunosuppressive TME, enhances tumor growth and immune evasion

The table is organized by epigenetic mechanism, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling. It focuses on how these alterations regulate immune-related gene expression, antigen presentation, chemokine signaling, immune-cell infiltration, and tumor progression. HDAC: Histone deacetylase; EZH2: Enhancer of zeste homolog 2; HDACs: Histone deacetylases; TME: Tumor microenvironment; miRNA: MicroRNA; STAT1: Signal transducer and activator of transcription 1; PD-L1: Programmed death-ligand 1; lncRNAs: Long non-coding RNAs; SWI: Switch; SNF: Sucrose non-fermentable; ISWI: Imitation switch; CHD: Chromodomain helicase DNA-binding; INO80: Inositol requiring 80.

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
MDSCs	H3K4 trimethylation; WDR5-dependent histone modifications	Opn promoter and other immunosuppressive mediators	Enhances secretion of immunosuppressive molecules; promotes recruitment of MDSCs to the tumor	Maintains immune suppression, reduces T-cell cytotoxicity, contributes to resistance to immunotherapy
Tregs	DNA methylation; histone deacetylation	Genes regulating Treg differentiation and suppressive function	Promotes accumulation and functional activity of Tregs within the tumor microenvironment	Exacerbates immune suppression and maintains immunosuppressive cell populations
General epigenetic-immune crosstalk	Combination of DNA/histone modifications and non-coding RNAs	Immune checkpoint genes, cytokine genes, regulatory genes in Tregs, MDSCs, TAMs	Epigenetic changes alter immune cell behavior, and immune activity can modify tumor epigenetics	Establishes immunosuppressive tumor microenvironment, contributes to T-cell dysfunction and therapy resistance

This table is organized by immune component. It highlights how epigenetic alterations affect immune checkpoint pathways, tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and related immunosuppressive mechanisms, with emphasis on therapeutic implications. CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; MDSC: Myeloid-derived suppressor cell; TAM: Tumor-associated macrophage; Opn: Osteopontin; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; WDR5: WD repeat-containing protein 5; CTLA-4: Cytotoxic T-lymphocyte associated protein 4; KMT2: Lysine methyltransferase 2; TGF-β: Transforming growth factor beta; IL-10: Interleukin-10; Tregs: Regulatory T Cells.