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.