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

Figure 1 Bidirectional crosstalk between autonomic nerves and key cellular components of the perineural tumor microenvironment in pancreatic ductal adenocarcinoma. Nerve terminals release norepinephrine, neuropeptides, and acetylcholine to modulate tumor-associated macrophages, tumor-associated neutrophils, myeloid-derived suppressor cells, cancer-associated fibroblasts, and cancer cells, collectively promoting immunosuppression, neural remodeling, and perineural invasion. Reciprocally, cellular compartments and associated Schwann cells secrete neurotrophic factors including nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and artemin that sustain axonal sprouting and reinforce the pro-invasive perineural niche. TAMs: Tumor-associated macrophages; TANs: Tumor-associated neutrophils; MDSCs: Myeloid-derived suppressor cells; CAFs: Cancer-associated fibroblasts; NGF: Nerve growth factor; BDNF: Brain-derived neurotrophic factor; GDNF: Glial cell line-derived neurotrophic factor; MMP: Matrix metalloproteinase; NETs: Neutrophil extracellular traps; PGE2: Prostaglandin E2; TNF-α: Tumor necrosis factor-α.

Figure 2 Activated Schwann cells serve as central orchestrators of perineural invasion in pancreatic ductal adenocarcinoma. They secrete neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor to drive neural remodeling, while matrix metalloproteinase-2, matrix metalloproteinase-9, and L1-cell adhesion molecule degrade the perineural extracellular matrix to facilitate tumor cell entry. Schwann cell-derived CCL2, CXCL12, and interleukin-6 further recruit immune cells and guide tumor cell migration along nerve trunks toward the celiac plexus. NGF: Nerve growth factor; BDNF: Brain-derived neurotrophic factor; GDNF: Glial cell line-derived neurotrophic factor; NT-3: Neurotrophin-3; IL: Interleukin; TGF-β: Transforming growth factor-β; TNF-α: Tumor necrosis factor-α; PNI: Perineural invasion; ECM: Extracellular matrix; MMP: Matrix metalloproteinase; CAM: Cell adhesion molecule.

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.