Beyond the synapses: should we anticipate neurotransmitter signaling when manufacturing CAR-T cells for brain tumors?

Brain tumors remain among the most challenging solid tumors to treat. Progress in Chimeric Antigen Receptor T (CAR-T) cell-based therapy in patients with hematological malignancies has offered an increasing interest in using this approach in brain tumors. However, multiple limitations are still challenging their translational application. Recent advances in cancer neuroscience showed that neurotransmitters can modulate T-cell anti-tumor immunity through activation, differentiation, trafficking, and checkpoint dependence. To date, research findings on how neurotransmitters modulate T cells are mainly limited to peripheral tumors, which are likely to be meaningfully different than locally in the brain. This perspective article highlights the strategic importance of considering local neurotransmitters in the brain when manufacturing CAR-T cells for brain tumors. Such a strategy will enable researchers to engineer cells not only against tumor antigens, but also against the specific signaling and metabolic pressures imposed by the brain microenvironment. Integrating brain regional neurochemical profiling into CAR-T design may ultimately support precision neuro-immunotherapy for brain tumors and demonstrate treatment optimization particularly in patients under neuromodulator drugs.