Neuro-immune-tumor microenvironment interactions in pancreatic cancer: mechanisms and targeted therapeutic strategies

Abstract Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is highly aggressive and resistant to conventional treatment. Perineural invasion (PNI) and bidirectional neuroimmune signaling contribute to tumor progression, immune evasion, pain, and treatment resistance. This review integrates the morphological and molecular basis of neural remodeling with reciprocal interactions among tumor, immune, stromal, and neural cells. We compare adrenergic, cholinergic, and sensory-neuropeptide pathways; connect local PNI with systemic cachexia circuits; and assess candidate biomarkers, multi-omics and liquid-biopsy approaches, and mechanism-based therapeutic strategies. By distinguishing preclinical, case-level, observational, and clinical-trial evidence, we provide a PDAC-specific framework spanning mechanism to translation. Most neuroimmune interventions remain preclinical or in early clinical development, and emerging targets, including vitamin D-binding protein, leukemia inhibitory factor, and growth differentiation factor 15, require independent replication and prospective PDAC validation before their clinical utility can be established.