Integrating neuroscience and oncology: neuroimmune crosstalk in the initiation and progression of digestive system tumors

Abstract

Recent global data show that cancers of the digestive system are responsible for approximately one-third of all cancer-related deaths worldwide, underscoring the urgent need for innovative therapeutic strategies. In this context, emerging findings from neuroscience may unveil new avenues for tackling this pressing clinical problem. Over the past few years, rapid progress in cancer neuroscience has increasingly underscored the contribution of the nervous system to the development and progression of digestive tract tumors. Research has shown that the specialized neural network of the gastrointestinal tract establishes a framework for reciprocal interactions with digestive tract tumors. On this anatomical foundation, our review delves into the functional significance of these interactions, emphasizing the bidirectional regulatory pathways between the nervous system and tumor cells during disease progression and highlighting their intricate crosstalk with the immune microenvironment. In particular, it maps the molecular pathways by which both the central and peripheral nervous systems (PNS) modulate tumor initiation and progression. Moreover, it explains how neurotransmitters and neuroendocrine mediators drive tumor expansion through the activation of canonical oncogenic signaling cascades and the remodeling of the immunosuppressive microenvironment. This review seeks to elucidate the molecular underpinnings of neuro-immune-tumor crosstalk and to synthesize the latest neural-targeted therapeutic approaches. It also examines the principal obstacles that are impeding the clinical implementation of these interventions. By presenting an integrated overview, this work serves as a robust resource to inform future studies on neurobiological mechanisms and the development of novel therapies for gastrointestinal malignancies.

Keywords: Cancer neuroscience; Digestive system tumors; Neuro-targeted therapy; Neuroendocrine mediators; Neuroimmune crosstalk; Tumor microenvironment.

Fig. 1

Innervation characteristics of the digestive system. Schematic diagram illustrating the innervation patterns across distinct organs in the digestive system and detailing the unique features of the enteric nervous system (ENS), thereby establishing an anatomical foundation for understanding the interplay between digestive system tumors and neural networks

Fig. 2

Interactions between the CNS and digestive system tumor. (1) The immunomodulatory role of specialized functional brain regions within the CNS. (2) The regulation of anti-tumor immunity by the classic HPA axis. (3) The modulation of tumor behavior and phenotype by non-classical stress hormones. (4) The immune modulation of SAS. (5) The regulatory pathway mechanisms of the gut-brain axis

Fig. 3

Sympathetic nervous system-immune cells interactions in the TME. Schematic diagram illustrating the differential immunomodulatory effects of the sympathetic nervous system on various immune cells within the digestive system tumor immune microenvironment, where the left side represents anti-tumor immunoregulation and the right side represents pro-tumor immunoregulation

Fig. 4

Parasympathetic nervous system and nociceptors-immune cells interactions in the TME. Schematic diagram illustrating the immunoregulatory roles of the parasympathetic nerves and nociceptors in the tumor immune microenvironment of the digestive system. The top left depicts the antitumor modulation by the parasympathetic nerves. The top right depicts the antitumor immune regulation by nociceptors. The bottom depicts the protumor immune modulation by nociceptors

Fig. 5

Summary of integration between classic tumor signaling pathways and neural signaling pathways. Schematic diagram illustrating interactions between multiple neural signaling pathways and distinct oncogenic tumor signals: a single neural pathway can activate several oncogenic signals, and conversely, a single oncogenic signal can be activated by multiple neural pathways, highlighting the complexity of nerve-tumor signal communication

Fig. 6

Neuro-immune-digestive system tumor interaction network. Schematic diagram illustrating the interactions among the CNS, PNS, ENS, immune cells, and tumor cells, and this complex neuro-immune-tumor regulatory network lays the groundwork for neuro-immune-tumor discipline