Neuro–immune interactions in colorectal cancer: mechanistic insights and therapeutic implications within the tumor immune microenvironment

Abstract

Within the CRC microenvironment, neural and immunological systems constitute a regulatory axis with strong dynamism and bidirectionality, thereby profoundly influencing tumor initiation, immune evasion, and therapeutic resistance. Here, we systematically outline the anatomical as well as functional underpinnings, the molecular mechanisms, and the translational potential of neuro–immune crosstalk within CRC. A unique biological context is offered by the gut, which houses two key components: an autonomous “second brain”, namely the enteric nervous system (ENS), and the human body’s largest immune organ. Consequently, this arrangement provides a natural platform supporting intensive neuro–immune crosstalk. At the central level, the classical brain–gut axis provides the physiological framework through which neuroendocrine and autonomic signals regulate intestinal and systemic immunity. Tumor-derived signals may functionally rewire this pre-existing network, thereby establishing a tumor–brain–immune circuit characterized by reciprocal signaling and positive-feedback amplification. In the periphery, nerve fibers of sympathetic, parasympathetic, and sensory origins regulate immune cell functions via neurotransmitters and neuropeptides—including norepinephrine, acetylcholine, CGRP, and substance P—which in turn drives immune suppression or tolerance. By contrast, neuronal activity and plasticity are modulated by immune cells through the production of neurotransmitter-like molecules and cytokines including IL-17A. In this process, glial cells—Schwann cells among them—serve as critical intermediaries. Given this context, emerging therapies directed against the neuro–immune axis include repurposed β-adrenergic blockers and neuropeptide receptor antagonists, together with neuromodulatory interventions such as vagus nerve stimulation and microbiota-based approaches. These therapies are promising avenues to overcome resistance to immunotherapy and to remodel the immune microenvironment of the tumor. It will be necessary for future investigations to integrate multi-omics profiling with precise neuromodulation technologies, so as to construct high-resolution maps of neuro–immune interactions and to advance interventions towards nerve subtype–specific precision. Ultimately, this effort will shift CRC treatment paradigms from immune precision toward neuro–immune precision.