Glutamate receptor–T cell receptor signaling potentiates full CD8+ T cell activation and effector function in tumor immunity

<h2>Summary</h2> Glutamate is best known as an excitatory neurotransmitter. However, its roles in T cell immunity remain underrecognized. We investigated the interplay between glutamate receptors (GluRs) and T cell receptors (TCRs) during CD8⁺ T cell activation. Our findings reveal that GluR expression in CD8⁺ T lymphocytes strongly correlates with the activation of TCR-CD28 signaling, enhancing their antitumor effector responses. Conversely, pharmacologic antagonism of GluRs in activated CD8⁺ T cells disrupts the colocalization of GluR with TCRVβ8.1, reduces the phosphorylation of TCR-signaling intermediates, alters calcium flux, and impairs the metabolic switch to glycolysis essential for T cell activation. Moreover, these disruptions blunt clonal proliferation and compromise the tumor-cytolytic capacity of CD8⁺ T cells. Thus, the glutamatergic system—<i>via</i> the GluR−TCR signaling complex—plays a critical amplifier role in activating CD8⁺ T cells and eliciting their full antitumor activity. This mechanistic insight reveals a previously underappreciated axis in T cell biology and opens avenues for immunotherapy regimens targeting GluR−TCR interactions to augment T cell–mediated responses in cancer and potentially other immunopathologies. <h3>Video Abstract</h3>