The Neuroimmune Axis in Gastric Cancer: Bridging Neural Regulation, Tumor Microenvironment, and Immunotherapy

Accumulating evidence indicates that the neuro-immune axis is central to gastric cancer pathogenesis. Dynamic, bidirectional signaling between neural circuits and immune cells promotes tumor progression, shapes an immunosuppressive microenvironment, and contributes to therapeutic resistance. We synthesize current knowledge on how autonomic (sympathetic and parasympathetic) and sensory innervation regulate gastric cancer biology. These circuits act through neurotransmitters (catecholamines, acetylcholine) and neuropeptides (substance P [SP], calcitonin gene-related peptide [CGRP]) to foster tumor growth and angiogenesis, facilitate perineural invasion, and enable immune evasion by recruiting suppressive myeloid and lymphoid populations and by inducing checkpoint molecule expression. We also examine how chronic stress and the microbiota-gut-brain axis intensify immunosuppression via glucocorticoid signaling and microbially derived metabolites. In parallel, we discuss why current immunotherapies achieve only modest response rates (approximately 10%-20%) in many settings, emphasizing neurally mediated mechanisms of resistance. We evaluate therapeutic strategies that target the neuro-immune axis-including pharmacological neuromodulation, selective neural ablation, and rational combination regimens-and outline how single-cell approaches and neural-tumor-microenvironment organoid models can accelerate mechanism-driven translation. This review aims to integrate current evidence from neuroscience and immuno-oncology to construct a conceptual framework for neuro-immune regulation in gastric cancer and to identify potential therapeutic strategies to overcome treatment resistance by targeting neural-tumor-immune crosstalk.