Mechanisms of neuropeptide-mediated immune sensing in the modulation of antitumor immunity.

The hallmarks of cancer, first introduced by Hanahan and Weinberg in 2000 and updated in 2011 and in 2022, summarize the core processes that drive the stepwise development of tumors. This framework has proven highly effective for interpreting the vast complexity of cancer and its underlying biology. However, advances in spatially resolved single-cell technologies and more advanced imaging approaches have revealed additional layers of regulation that shape tumor behavior, particularly involving interactions between tumors and the nervous system. Although the influence of innervation on tumor cells and tumor vasculature has been widely studied, the impact of neurotransmitters, neural-derived factors, or neuropeptides on tumor-infiltrating immune cells remains largely unexplored and unexploited. Importantly, immune cells within the tumor microenvironment express receptors for various neural-derived signals, and can shift their phenotypes and adapt their functions in response to these inputs. Here, we highlight neuropeptide-driven pathways that modulate tumor-infiltrating immune cells to influence hallmark functions and, ultimately, shape tumor progression. Neural regulation of the tumor microenvironment is therefore emerging as a promising and potentially targetable layer that could complement existing cancer therapies.