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

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.