Dongyao Zhang, Speaker at Oncology Conferences

Shanghai, China

Title : Mechanistic study on the activation of primary motor cortex (M1) in inhibiting ovarian cancer through IGLUR-mediated reversal of CD8⁺ T cell exhaustion

Abstract:

Objective: Ovarian cancer (OC) immunosuppression severely limits therapeutic efficacy. While peripheral neural tumor regulation is recognized, the central nervous system's (CNS) role in modulating the tumor immune microenvironment (TIME) remains unclear. We aimed to map the primary motor cortex (M1)-ovary neural connection and elucidate how M1 activation regulates OC progression and CD8? T cell function.
Methods: PRV retrograde tracing mapped the brain-ovary circuit, and chemogenetics modulated M1 excitability in an orthotopic ID8-luc mouse OC model. Tumor-infiltrating CD8? T cells were analyzed via scRNA-seq and flow cytometry. TME neurotransmitters were assessed using LC-MS targeted metabolomics. The Glutamate-iGluR-Ca²? axis was investigated via real-time calcium imaging and CNQX pharmacological rescue.
Results: PRV tracing revealed a direct, contralateral neural projection from M1 to the ovary. Unilateral M1 activation significantly suppressed contralateral OC progression and extended survival, an effect completely abolished by CD8? T cell depletion. M1 activation reinvigorated immunity by reducing CD8? T cell exhaustion (downregulating PD-1/TIM-3) and enhancing effector molecules (GZMB, TNF-α). Metabolomics showed M1 activation significantly decreased TME L-glutamate levels, which correlated with tumor burden. Mechanistically, high TME glutamate drove pathological TCR-mediated calcium overload via ionotropic glutamate
receptors (iGluRs, specifically GRIK5) on T cells. Pharmacological iGluR blockade completely rescued this glutamate-induced T cell dysfunction.
Conclusion: We reveal a previously unrecognized descending axis by which higher brain centers regulate peripheral tumor progression: M1 activation remodels the TME metabolic landscape by reducing glutamate concentration, thereby blocking iGluR-mediated CD8? T cell exhaustion and reinvigorating anti-tumor immunity. These findings provide a novel theoretical framework and CNS-targeted therapeutic strategy for OC.
Key words: Ovarian Cancer, Primary Motor Corte, CD8+ T Cell Exhaustion, Ionotropic
Glutamate Receptors, Cancer Neuroscience

Biography:

Dongyao Zhang is a researcher in Obstetrics and Gynecology at Shanghai Jiao Tong University School of Medicine. His research focuses on gynecologic oncology, tumor metabolism, reproductive metabolism, and the tumor immune microenvironment. He has published multiple first-author studies in JCR Q1/Q2 journals, with a cumulative impact factor exceeding 26 based on his listed publications. His current work investigates metabolic and neuroimmune mechanisms in ovarian cancer, with particular interest in amino acid metabolism, CD8⁺ T-cell dysfunction, and novel therapeutic targets.