Prominent crosstalks between perineural invasion and immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma

Figure 3 Schematic illustration of targeting the neural-immune axis in perineural invasion-positive pancreatic ductal adenocarcinoma. Neural-targeted therapies including β-adrenergic blockade, tropomyosin receptor kinase A/nerve growth factor inhibition, and RET/glial cell line-derived neurotrophic factor inhibition suppress sympathetic-driven immunosuppression, axonal sprouting, and Schwann cell-directed tumor invasion. Combined stromal-myeloid targeting and immunotherapy disrupts the immunosuppressive perineural niche by depleting myeloid-derived suppressor cells and tumor-associated neutrophils, activating dendritic cell, and stimulating CD8+ T cells at the invasive neural front. TrkA: Tropomyosin receptor kinase A; NGF: Nerve growth factor; PNI: Perineural invasion; TAM: Tumor-associated macrophage; ECM: Extracellular matrix; GDNF: Glial cell line-derived neurotrophic factor; CAF: Cancer-associated fibroblast; PDAC: Pancreatic ductal adenocarcinoma.