Gastric cancer in the Era of neural regulation

Neural regulation of gastric cancer (GC) has conventionally been parsed into isolated axes-vagal, sympathetic, or sensory. This compartmentalized view is increasingly untenable. The stomach is embedded in a multilayered neural architecture in which tumor-infiltrating nerves, the enteric nervous system (ENS), and long-range brain-gut pathways operate at distinct yet interconnected spatial scales. These layers do not simply deliver unidirectional "nerve-to-tumor" commands; they dynamically shape epithelial behavior, stromal and immune states, organ physiology, and ultimately treatment responses. Here we propose a three-level framework for neural regulation in GC: local neural remodeling within tumors, the ENS as an intrinsic organ-level network, and central control through brain-gut axes. Within this framework, we emphasize that the same neural pathway can exert opposing effects depending on disease stage, anatomical compartment, neuronal subtype, and the prevailing microenvironmental and systemic context. Critically, neural regulation must be understood as a bidirectional, multi-modal dialogue: nerves modulate every cellular compartment of the tumor microenvironment (TME), while TME components (e.g. cancer cells, immune infiltrates, vascular endothelium, and fibroblasts) reciprocally remodel neural architecture and function. This dialogue is further conditioned by macroenvironmental factors (psychosocial stress, dietary metabolism, and gut microbiota) and local physicochemical cues (mechanical forces, epigenetic states, metabolites, secreted protein signals, and even cell-surface RNAs). Unraveling this complexity will require not only classical neural tracing but also a new generation of technologies-tissue-specific secretomes, in vivo cell-cell interaction labeling, and cell-surface nucleic-acid sequencing at single-cell resolution.