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Life sciences · Journal article
Journal of Biomolecules Pathogenesis and Therapeutics · September 17, 2026
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Immune and stromal factors are not the only factors that create the tumor microenvironment (TME) because neuromodulatory signals can also change tumor biology. Classical neurotransmitters of the central nervous system, dopamine and glutamate, are becoming known to have an active role in tumor progression, immune modulation, angiogenesis, and metabolic reprogramming of the TME. Dopamine receptors enable dopaminergic to regulate tumor cell proliferation, vascular permeability, and recruitment/activation of immune cells, and glutamatergic to regulate cancer-cell bioenergetics, migration, and excitatory paracrine interactions with stromal cells. Preclinical evidence indicates that receptor heterogeneity, setting-dependent effects, and possible neurotoxicity make it difficult to translate findings from preclinical studies that propose that manipulation of such pathways can sensitize tumors to chemotherapy and immunotherapy. The objective is to summarize existing mechanistic understanding of the roles of dopamine and glutamate in the TME, assess the therapeutic interventions to target the receptors or modulate the metabolism, and outline the main challenges that the biomarker choice, spatial heterogeneity, and safety need to be overcome to develop neuromodulatory oncology. Neurotransmitter network targeting is an exciting, but challenging, area that would add value to the currently available TME-directed therapies and increase the precision of the oncology group.