<p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, primarily due to its highly fibrotic and immunosuppressive tumor microenvironment (TME), which limits both drug delivery and immune cell infiltration. Epigenetic dysregulation plays a pivotal role in shaping these barriers by controlling transcriptional programs that govern tumor-immune interactions, stromal remodeling, and immune evasion.</p><p>This review synthesizes current insights into the contribution of aberrant epigenetic mechanisms to PDAC progression and immune resistance. We outline how epigenetic alterations suppress antigen presentation, sustain immunosuppressive cell populations, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and upregulate immune checkpoint molecules across cancer and stromal compartments. Emerging evidence shows that epigenetic therapies targeting DNA methyltransferases, histone deacetylases, histone methyltransferases, or bromodomain proteins can restore tumor immunogenicity, reprogram cancer-associated fibroblasts, and promote cytotoxic T cell infiltration. Furthermore, combining epigenetic modulators with immune checkpoint blockade or targeted therapies has demonstrated the capacity to remodel the PDAC TME and convert immunologically ‘cold’ tumors into more responsive ones. Therefore, we also summarize key completed and ongoing clinical trials in PDAC and solid tumors, emphasizing outcomes and biomarker discoveries that support the translation of epigenetic-immunotherapy combinations into clinical practice. Finally, we discuss persistent challenges that impede progress, including poor drug penetration through the desmoplastic stroma, off-target effects and toxicity of epigenetic agents, tumor hypoxia, adaptive resistance, and the scarcity of physiologically relevant immuno-oncology models.</p><p>Findings from preclinical and early clinical studies indicate that epigenetic reprogramming represents a promising avenue to overcome PDAC immunoresistance by reactivating antigen presentation, disrupting immunosuppressive cellular networks, and enhancing antitumor immunity. However, realizing this potential will require rationally designed combination regimens, predictive biomarkers for patient stratification, and a deeper understanding of cell type-specific and context-dependent epigenetic regulation. Only through these advances can the integration of epigenetic modulation with immunotherapy and stroma-targeting approaches ultimately redefine therapeutic strategies for patients with PDAC.</p>