IMMU-68. Glioblastoma co-opts dural nociceptors to drive immune evasion and immunotherapy resistance

Abstract Glioblastoma (GB) is recalcitrant to immunotherapy due to severe CD8⁺ T cell exclusion and abundance of immunosuppressive tumor-associated macrophages (TAMs). Defining the mechanisms of immune evasion in GB is essential for identifying therapeutic vulnerabilities. Here, we unveil dural nociceptors—pain-sensing sensory neurons—as critical, noncanonical drivers of immune evasion in GB. We demonstrate that dural nociceptors are activated and reprogrammed by soluble factors present in GB-associated cerebrospinal fluid. In syngeneic orthotopic GB murine models, ablation of nociceptors significantly improves survival, enhances anti-tumor immune responses, and sensitizes otherwise unresponsive tumors to immune checkpoint blockade therapy (ICBT). Mechanistically, GB-associated dural nociceptors secrete elevated levels of the immunomodulatory neuropeptide calcitonin gene-related peptide (CGRP). Single-cell RNA-sequencing analyses of human GB samples show that RAMP1, the receptor subunit for CGRP, is selectively expressed on TAM subsets with pronounced immunosuppressive features. Using macrophage-specific RAMP1 conditional knockout (cKO) mice, we found that RAMP1 deletion in TAMs significantly prolongs survival of GB-bearing mice, reduces TAM immunosuppression, and enhances CD8⁺ T cell infiltration and effector function while limiting exhaustion. This survival benefit is lost with CD8⁺ T cell depletion, highlighting the key role of CGRP-driven TAM–T cell crosstalk in shaping anti-tumor immunity. Importantly, GB-bearing cKO mice exhibit markedly improved responsiveness to ICBT. At the molecular level, we uncover a strong reciprocal antagonism between CGRP and interferon-gamma (IFN-γ) signaling that dictates TAM fate. CGRP inhibits IFN-γ–induced STAT1 activation, while IFN-γ blocks CGRP-driven cAMP levels and downregulates RAMP1 expression. CGRP acts as a neural cue that imprints immunosuppressive features in TAMs by blocking their sensitivity to IFN-γ, a critical pro-inflammatory cytokine required for anti-tumor immunity, at transcriptional and epigenetic levels. Thus, the CGRP–RAMP1 axis represents a hijacked neural circuit driving immune evasion in GB and offers a translatable strategy to restore immunotherapy response by repurposing FDA-approved CGRP antagonists.