Neurotransmitters critically modulate tumor progression and immune evasion, revealing novel therapeutic targets in cancer.

The complex interplay between the nervous system and cancer, termed neuro-oncology, is a rapidly evolving field. Traditional cancer therapies often overlook the profound influence of neural signaling on tumor biology. Tumor immunomodulation and metastasis are significantly impacted by neurotransmitters, which act via autocrine/paracrine pathways and receptor-mediated interactions. Understanding these mechanisms is crucial for developing advanced, integrated cancer treatments that address the limitations of current standards of care, which often fail to account for the dynamic tumor microenvironment and its neural components.

This comprehensive review synthesizes mechanistic insights from recent studies on neurotransmitter-mediated regulation of the tumor microenvironment. It classifies neurotransmitters into cholinergic agents, monoamines, amino acids, and peptides, examining their roles in tumorigenesis, metastasis, and immune evasion. The authors analyzed how these molecules influence tumor cell proliferation, apoptosis, and immune cell activity by modulating intracellular signaling cascades through specific posttranslational modifications like serotonylation and dopaminylation. The review also explores emerging pharmacological interventions and novel therapeutic strategies, including tumor vaccines.

Neurotransmitters exhibit multifaceted and often dual roles in cancer progression. For instance, serotonin enhances glycolysis in CD8+ T cells, thereby potentiating antitumor responses. Conversely, γ-aminobutyric acid (GABA) accumulates within tumors, actively promoting immune escape mechanisms. Receptor signaling and posttranslational modifications, such as serotonylation and dopaminylation, are key modulators of intracellular cascades influencing tumor cell proliferation and apoptosis. The review highlights that:

Pharmacological interventions targeting neurotransmitter synthesis, release, or receptor signaling, particularly when combined with immune checkpoint inhibitors, have resulted in improved clinical outcomes. Additionally, neurotransmitter-driven tumor vaccines represent a promising frontier, leveraging these neuromodulatory pathways to optimize immunotherapy. These findings collectively provide a translational framework for integrating neuroimmune crosstalk into precision oncology.