Neuro-immune interactions in gastrointestinal oncology: Mechanisms, challenges, and therapeutic potential

Public summary

* Neuroimmune interactions in the gastrointestinal tract fundamentally shape tumor initiation and progression.

* Dynamic crosstalk among nerves, immune cells, and cancer cells orchestrates gastrointestinal tumorigenesis.

* Central, sensory, autonomic, and enteric nervous systems regulate tumor immunity via diverse signaling pathways.

* Targeting neuroimmune circuits offers novel therapeutic avenues for managing gastrointestinal cancers.

Abstract

Gastrointestinal (GI) cancers represent a leading cause of cancer-related mortality globally, characterized by a complex tumor microenvironment where bidirectional neuro-cancer-immune interactions critically influence disease progression. The CNS integrates ascending gut-derived signals and transmits descending regulatory responses through distinct autonomic neural pathways, while peripheral sensory, sympathetic, parasympathetic, and enteric neurons modulate innate and adaptive immune cell functions through specialized neurotransmitter circuits. This coordinated neural-immune crosstalk operates within the neuro-endocrine-immune axis, forming an integrated regulatory network that governs tissue homeostasis and tumor surveillance. Emerging evidence demonstrates that neural dysregulation promotes GI tumorigenesis through immunosuppressive mechanisms, while therapeutic neural interventions show promising efficacy in preclinical cancer models. The gut-brain axis represents a paradigmatic framework for understanding how neuroimmune signaling influences cancer progression and metastasis, revealing previously unrecognized diagnostic, prognostic, and therapeutic opportunities. Here, we review the molecular mechanisms underlying neuroimmune interactions in GI cancer pathogenesis and evaluate the therapeutic potential of neurally targeted interventions for cancer management.