Peritoneal metastasis in pancreatic cancer: molecular mechanisms, microenvironmental remodeling, and emerging...

Pancreatic cancer remains one of the most lethal malignancies, and its frequent spread to the peritoneum significantly compromises patient survival and quality of life. Peritoneal metastasis arises from a complex interaction between tumor intrinsic features and the unique anatomical and immune environment of the peritoneal cavity. This review systematically elucidates the stepwise process of peritoneal dissemination, including initial cell detachment, epithelial-to-mesenchymal transition, resistance to anoikis, immune evasion, adhesion to the mesothelium, and angiogenesis. We then highlight four interconnected regulatory hubs that drive these events: metabolic reprogramming that supports tumor survival and reinforces immune suppression; extracellular vesicles that enable intercellular communication and premetastatic niche formation; cancer stem cells that confer phenotypic flexibility and therapy resistance; and the dynamically remodeled immune microenvironment that facilitates tumor colonization. Finally, we critically assess emerging locoregional treatment strategies, namely normothermic, hyperthermic, and pressurized intraperitoneal chemotherapy, designed to overcome the peritoneal-plasma barrier and improve clinical outcomes. Furthermore, we evaluate the potential synergistic effects of integrating these strategies with immunotherapy. By synthesizing current knowledge of the molecular and cellular mechanisms underlying peritoneal metastasis in pancreatic cancer, this review offers a conceptual framework for developing precision-targeted interventions against this devastating condition.