Decoding Dural Nociceptors as Drivers of Immune Suppression in Glioblastoma

(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 culture assays, single-nucleus and single-cell RNA sequencing (snRNA-seq, scRNA-seq), multi-dimensional flow cytometry, and survival studies under conditions of immune perturbation. These approaches will elucidate the tumor-derived factors that modulate nociceptors and define the bidirectional interactions between nociceptors and immune cells within the TME, revealing the mechanisms by which these neurons regulate anti-tumor immunity. Beyond advancing fundamental understanding, this work holds significant therapeutic potential. By targeting nociceptor-driven immune regulation, we aim to develop strategies to reverse immune suppression in GB, including repurposing existing nociceptor-targeting therapies to enhance efficacy of immunotherapies. Ultimately, our goal is to uncover new therapeutic avenues for improving survival outcomes in patients with this devastating disease. Project Number: 1R21CA309473-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Nandini Acharya | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $390,906 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BTC-F (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288383