Immuno-Neural Mechanisms in Gastrointestinal Tumorigenesis: Bridging Inflammation, Neural Regulation, and Therapeutic Innovation

Yan Zhao¹Ji-Feng Sui²Dong Ning Wu^3,4Min Chen³金霞 倪⁵Yue Zhang⁴Shi-Yong Xin^6*Meng-nan Fan^6*

• ¹Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
• ²Liaoning University of Traditional Chinese Medicine Affiliated Hospital, Shenyang, China
• ³Macau University of Science and Technology, Taipa, Macao, SAR China
• ⁴China Academy of Chinese Medical Sciences Guang'anmen Hospital, Beijing, China
• ⁵Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, China
• ⁶Tianjin University of Traditional Chinese Medicine Second Affiliated Hospital, Tianjin, China

Gastrointestinal (GI) tumors remain a leading cause of global cancer mortality, with late-stage diagnosis and metastatic dissemination posing major clinical challenges. This review synthesizes current understanding of the intricate interplay between immune regulation, neural signaling, and tumor microenvironment dynamics in GI malignancies. We highlight how chronic inflammation, driven by pathogens like H. pylori or inflammatory bowel disease, establishes a pro-tumorigenic milieu through cytokine networks (IL-1β, TNF-α, IL-6) and Wnt/β-catenin signaling, while neural components (serotonergic, cholinergic, and peptidergic pathways) actively participate in cancer progression via neurotrophic factors and neurotransmitter-mediated crosstalk. Emerging evidence reveals that colorectal cancer stem cells exploit neuronal signaling (particularly 5-HT/Wnt activation) for self-renewal, and that perineural invasion serves as a critical metastatic route. The dual role of immune cells is explored, with macrophages (M1/M2 polarization), T cells, and neutrophils exhibiting both tumor-suppressive and pro-metastatic functions depending on context. We evaluate recent therapeutic advances including immune checkpoint inhibitors, CAR T-cell therapies, and neural-targeted approaches, while addressing limitations such as chemoresistance and immune-related adverse events. The potential of microbiota modulation and nanotechnology for precision therapy is discussed. By integrating molecular mechanisms with clinical observations, this work proposes that combinatorial strategies targeting immuno-neural axes may overcome current treatment barriers, emphasizing the need for early detection and personalized approaches in GI oncology.