Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma

Abstract

Glioblastomas (GBMs) are uniformly fatal brain tumors resistant to immunotherapy, yet the mechanisms driving immune dysfunction remain poorly understood. Here we identify a tissue-specific mechanism of dendritic cell (DC) dysfunction contributing to GBM immune evasion. We demonstrate that while systemic immunity depends on type 1 conventional DCs (cDC1s), GBMs preferentially accumulate cDC2s with impaired antigen-presenting capacity. Further, microglia-derived GAS6 and PROS1 signaling through the AXL receptor on DCs suppresses DC activation and, critically, migration to tumor-draining lymph nodes. Pharmacologic AXL inhibition enhances DC migration and consequently anti-tumor immunity. Importantly, radiation therapy activates cDC1-mediated endogenous immune responses, which synergizes with mRNA vaccination to promote complete and durable immune-mediated tumor regression. These findings establish DC-mediated immunity as a therapeutic target in brain tumors and reveal a synergistic mechanism for combining radiation with personalized cancer vaccines.