Decoding the neuroimmune axis in colorectal cancer: From neural circuitry to therapeutic innovation

The nervous and immune systems are two major components that maintain body homeostasis, with their functional roles often overlapping significantly. Both systems are capable of identifying, integrating, and organizing responsive reactions to various external stimuli. The gut, referred to as the "second brain" and the largest immune organ in the body, serves as the most frequent focal site for neuroimmune interactions. Colorectal cancer (CRC), as the predominant solid tumor arising in this neuroimmune-rich microenvironment, remains understudied through the lens of neuroimmune regulatory mechanisms. This review systematically synthesizes current evidence to elucidate the neuroimmune axis in CRC pathogenesis, with particular emphasis on neuroimmune crosstalk-mediated remodeling of tumor immunity. We comprehensively catalog the immunomodulatory effects exerted by principal neuroregulatory mediators, categorized as: (1) neurotransmitters (glutamate, glutamine, γ-aminobutyric acid, epinephrine, norepinephrine, dopamine, serotonin, acetylcholine, and gaseous signaling molecules); (2) neuropeptides (substance P, calcitonin gene-related peptide, vasoactive intestinal peptide); and (3) neurotrophic factors. Furthermore, we critically evaluate the translational prospects and therapeutic challenges of targeting neuroimmune pathways and propose strategic priorities and research focuses for advancing the development of neuroimmune interaction-related therapeutic approaches in CRC.