Design of nano-delivery systems for pancreatic cancer immunotherapy.

Often referred to as the "king of cancers" pancreatic cancer is a serious threat to public health, as most cases are diagnosed at an advanced stage. Although tumor immunotherapy is a major advancement in cancer treatment, its effectiveness in pancreatic cancer remains limited, particularly owing to the unique characteristics of the tumor microenvironment. Nano-delivery systems offer a promising approach for overcoming the dense stromal barrier, which is crucial for enhancing the therapeutic efficacy. In this review, we systematically summarize key immunotherapeutic targets, including cancer-associated fibroblast (CAF), immune cells (tumor-associated macrophage (TAM), myeloid-derived suppressor cell (MDSC), regulatory T cells (Treg), tumor-associated neutrophil (TAN), CD4T, CD8T cells), extracellular matrix (ECM), and discussed regulatory strategies in pancreatic cancer based on its pathogenesis and recent clinical advances to guide target selection. We then detail the physicochemical properties of nano-delivery systems suitable for pancreatic cancer and outline how tumor microenvironment-responsive linkers can enable particle size or charge conversion. Furthermore, we review the latest research progress on various nano-delivery systems (Lipid-based nanoparticle, Hydrogel/microneedle, Inorganic nanoparticle, Cancer vaccine, Adoptive cell therapy, Exosome/vesicle, Bacteria/virus) to inform the design of pancreatic cancer nanocarriers. Finally, we discuss future directions and summarize the challenges in translating pancreatic cancer nano-delivery systems into clinical practice. By integrating target identification, nanocarrier design, and clinical applications, we aimed to provide a cohesive framework that offers insights to accelerate the development of effective pancreatic cancer therapies.