<p><?tk 4?>Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, traditionally attributed to genetic mutations and epigenetic alterations. However, with the emergence of cancer neuroscience, a paradigm shift has occurred, revealing the central role of the nervous system in the initiation, progression, and metastasis of CRC. The gastrointestinal tract, being the only organ in the body with an independent peripheral nervous system — the enteric nervous system (ENS) — provides a unique anatomical and functional basis for neuro-tumor interactions. This review systematically explores the mechanisms by which the nervous system regulates CRC cell proliferation, invasion, and immune microenvironment remodeling through neurotransmitters (such as norepinephrine and acetylcholine) and neurotrophic factors (including NGF and BDNF). We also delve into the role of the brain-gut-microbiome axis, particularly its influence on tumor progression through metabolic reprogramming and neuroimmune crosstalk. Finally, we discuss novel therapeutic strategies based on the bidirectional communication between the nervous system and CRC, offering new perspectives for precise interventions in CRC.</p> Graphical Abstract <p></p>