TGF-β–YY1 signaling as a key driver of immune evasion in pancreatic cancer: Therapeutic implications

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by a dense desmoplastic stroma, profound immune suppression, and resistance to conventional therapeutics. Poor patient outcomes are driven by resistance to chemotherapy and immunotherapy arising from both tumor-intrinsic and microenvironmental mechanisms. Elucidating the molecular pathways underlying therapeutic failure is therefore critical. Transforming growth factor-β (TGF-β) is a central regulator of PDAC progression, promoting epithelial-mesenchymal-transition (EMT), stromal remodeling, immune exclusion, and checkpoint activation at advanced disease stages. The transcription factor Yin Yang 1 (YY1) is a critical downstream integrator and amplifier of TGF-β-driven signaling programs. YY1 reinforces EMT, metabolic adaptation, and immune evasion through transcriptional, epigenetic, and post-transcriptional regulations. Several key immune modulators of immune evasion include PD-L1, indoleamine 2,3-dioxygenase, FOXP3, and pro-tumoral chemokines. The coordinated TGF-β-YY1 signaling suppresses CD8 cytotoxic T-cell (CTL) and natural killer (NK) cell functions, promotes regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and establishes an immune-cold, therapy-resistant tumor microenvironment. This review explores the mechanistic basis of the TGF-β-YY1 cross-talk regulation in the immune evasion of PDAC. It also discusses emerging therapeutic opportunities in targeting the TGF-β-YY1 axis to overcome immune escape and improve treatment outcomes in PDAC.