Neurodegeneration of local sympathetic inputs promotes colorectal cancer progression

The nervous system can profoundly influence cancer prognosis, and this frontier of cancer neuroscience has increasingly garnered research attention. However, the involvement of neural signals in colorectal cancer remains incompletely understood. In this study, we exploit advanced three-dimensional imaging and conventional immunohistochemistry to observe a transitional loss of local sympathetic inputs from colorectal adenomas to adenocarcinomas in human patients. This negative correlation similarly occurs in the mouse models of colorectal cancer. Of importance, the pharmacologic ablation of sympathetic innervations significantly exaggerates the progression of colorectal tumors in the chemical-induced mouse model. We then demonstrate that the sympathetic neurotransmitter norepinephrine acts via α2-adrenergic receptors to elevate the cancer cell expression of chemokines to recruit CD8⁺ T cells, and the destruction of sympathetic signals leads to their reduction within the tumor microenvironment. Together, these results have elucidated a novel aspect of the neurodegeneration of local sympathetic inputs in promoting colorectal cancer progression.