Yang Chen, Xuejuan Wang
Historically, research about the TME has primarily focused on local cellular interactions. However, it is now established that the TME is governed by a highly dynamic, bidirectional communication network between the nervous system and the gut microbiota. Within this complex ecosystem, the gut microbiota serves as the primary source of signaling, continuously generating neuroactive substances such as SCFAs and tryptophan metabolites. These microbial cues do not act in isolation. Rather, they are first perceived and integrated by the host nervous system. Subsequently, acting as a signal amplifier and spatial orchestrator, the nervous system converts these integrated signals into systemic regulatory commands directed at the TME. Meanwhile, tumors are far from passive recipients. By secreting neurotrophic factors to induce local neoneurogenesis, and by triggering systemic stress responses, they actively participate in this dialogue. Coupled with the physical translocation and colonization of gut bacteria into the tumor interior, these processes collectively construct a self-amplifying gut-neuro-tumor signaling feedback. This article systematically explores the molecular mechanisms and dynamic evolution of this feedback, emphasizing the clinical potential of targeting this cross-system network as a druggable system. Multilevel interventions targeting this circuit pave the way for the next generation of paradigms in precision oncology combination therapies.