Crit Rev Oncog. 2026 ;31(1):
67-107
Neurotransmitters are critical signaling molecules of the nervous system that activate their receptors within milliseconds, and convey accurate, coordinated, tightly regulated and important messages from one nerve cell, across a synapse, to another nerve, muscle or gland cell. It is time to realize that specific neurotransmitters also activate T cells directly and rapidly via their receptors in T cells. Subsequently, they decrease immune checkpoint inhibitors, increase expression of critical receptors, and induce a kaleidoscope of effector T cell functions. This review summarizes our discoveries of direct, activating, rejuvenating, and strengthening effects of either Dopamine, Glutamate, GnRH-II or Neuropeptide Y, or their combinations on human T cells of five origins: (1) normal T cells of healthy people, (2) exhausted T cells of head and neck cancer patients, (3) exhausted T cells of hepatocellular carcinoma patients, (4) exhausted T cells of glioblastoma patients, and (5) human genetically-engineered CAR T cells. The beneficial effects of these neurotransmitters on healthy T cells and on exhausted T cells of cancer patients include the following: depolarization; simultaneous decreased expression of key checkpoint inhibitors (PD-1, LAG-3, Tim-3, TIGIT and CD160); increased expression of CD3 zeta chain, CD147/EMM-PRIN/Basigin and 67kDa laminin receptor; and increased adhesion to fibronectin and laminin, chemotactic migration to SDF-1, migration toward autologous tumors, gene expression, cytokine secretion, proliferation, and arrest of human cancer cells. The direct effects of GnRH-II, Dopamine, or Glutamate on human anti-breast cancer ErbB-2+ CAR T cells were discovered in a yet unpublished collaborative research with Professor Zelig Eshhar, the pioneering scientist who invented and developed the concept of T-bodies, later re-named CAR T cells. The direct effects of the neurotransmitters on these CAR T cells include (1) dramatically increased expression of: CD3 zeta, CD147 and CXCR4, within only 30 minutes; (2) increased chemotactic migration towards SDF-1; (3) increased migration toward breast cancer cells; (4) increased penetration of the bone marrow of SCID mice; (5) increased homing to human breast cancer in SCID mice; and (6) increased inhibition of human breast cancer in SCID mice. In summary, either Glutamate, Dopamine, Neuropeptide Y, GnRH-II or their combinations, can activate, rescue, and strengthen healthy, exhausted, and genetically engineered CAR T cells. A novel personalized adoptive immunotherapy, called Brain-iT Immunotherapy, was invented and patented, and the review details its diagnostic and therapeutic stages for either patient's exhausted T cells or genetically engineered CAR T cells.