Neuroimmune crosstalk in pancreatic ductal adenocarcinoma: integrating neuroscience and immuno-oncology

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and remains largely refractory to immunotherapy because of its profoundly immunosuppressive tumor microenvironment (TME). Emerging advances in cancer neuroscience suggest that immune resistance in PDAC may not be fully explained by immune-centered models alone, and increasingly implicate neural signaling as a potential context-dependent regulator of tumor progression and microenvironmental remodeling. In this review, we synthesize current evidence on the anatomical basis of pancreatic innervation, tumor-associated neural remodeling, and perineural invasion (PNI), and examine how these neural alterations are integrated with the immune landscape of PDAC. We summarize molecular pathways through which central and peripheral neural signals have been implicated in PDAC initiation, progression, and microenvironmental regulation, and further delineate how neural signaling shapes tumor development at the molecular and cellular levels by modulating immune-cell recruitment, functional polarization, and stromal interactions. Beyond direct neuroimmune regulation, we address an emerging regulatory layer: systemic metabolic states may precondition neural, immune, and stromal compartments. In parallel, neural signaling can intersect with tumor metabolic adaptation, potentially sustaining persistent immunosuppressive programs within the TME. Finally, we evaluate current and emerging therapeutic strategies targeting neural signaling and neuroimmune interactions, together with the major barriers limiting their clinical translation. By integrating perineural niche biology, spatial immune-stromal architecture, pathway-specific neural-metabolic coupling, and therapeutic translation, this review provides a PDAC-centered, evidence-aware narrative synthesis, and outlines candidate-marker-informed, safety-aware strategies for future investigation.