Figure 2. Neural communication in the TME.

Neurotrophins (NGF, BDNF), neurotransmitters (norepinephrine [NE], acetylcholine [ACh]), neuropeptides (SP, CGRP), and their cognate receptors modulate activity of cancer cells and components of the TME. Norepinephrine induces cancer cell proliferation and production of neurotrophins, while also inducing angiogenesis in endothelial cells and alternative (M₂) activation of macrophages. Neurotrophins further induce axonogenesis through activation of TrkA/B expressed on nerve cells. T cell activity and expression of cell death receptors (FAS/PD-1) on T cells and cancer cells (PD-L1) are modulated by neurotransmitters, altering tumor immunity within the TME. Stromal cells also respond to neuropeptides to alter ECM composition via expression of MMPs, which regulate invasion and metastasis.