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REVIEW

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

Fangyuan Zhang1,#, Xi Wang2,#, Xinxin Shen3, Pei Xiong3, Yan Yang4,*, Jincheng Wang5,*
1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310058, China
2 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
4 Department of Health Promotion, China Science and Technology, Development Center of Chinese Medicine, Beijing, 100023, China
5 Institute of Chinese Medicine Literature, Nanjing University of Chinese Medicine, Nanjing, 210023, China
* Corresponding Author: Yan Yang. Email: email; Jincheng Wang. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Transcriptome Analysis in Tumor Microenvironment and Tumor Heterogeneity)

Oncology Research https://doi.org/10.32604/or.2025.074893

Received 21 October 2025; Accepted 04 December 2025; Published online 29 December 2025

Abstract

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.

Keywords

Gastric cancer; neuro-immune axis; tumor microenvironment; adrenergic signaling; immunotherapy resistance; microbiota-gut-brain axis

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