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.