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), CD4⁺T, CD8⁺T 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.