Project Summary (Abstract): Glioblastoma (GB) remains one of the most lethal cancers, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the effectiveness of current immunotherapies. While research has heavily focused on traditional regulators of immune cells, nociceptors—pain-sensing sensory neurons known to regulate immune responses in the periphery—have not been studied in GB, creating a significant gap in our understanding of immune regulation in the disease. Of note, in the cranial region, nociceptors are densely concentrated in the dural layer of the meninges but are absent from the brain parenchyma. This anatomical separation from GB tumors has likely contributed to their historical neglect in GB research, overlooking their potential as critical regulators of anti-tumor immunity. Our preliminary data provide compelling evidence that nociceptors play an active role in GB pathogenesis. In syngeneic orthotopic GB mouse models, we observed heightened activation of dural nociceptors in the presence of tumors, marked by increased production of calcitonin gene-related peptide (CGRP), a neuropeptide with known immunomodulatory functions. Furthermore, cerebrospinal fluid (CSF) from GB-bearing mice promotes pronounced axonal elongation in cultured primary trigeminal nociceptors, indicating that tumor-derived factors can directly modulate these neurons. Strikingly, nociceptor ablation in GB-bearing mice leads to transformative changes: prolonged survival, a shift in the TME from an immune-suppressive ‘cold’ state to an immune-activating ‘hot’ state and enhanced responsiveness to immune checkpoint blockade (ICB) therapy. These findings demonstrate that nociceptors, despite their physical separation from the tumor, can remotely regulate GB progression by modulating the immune landscape. To elucidate the mechanisms underlying nociceptor-mediated immune regulation in GB, we are employing methodologies including ELISAs, in vitro neuronal