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

Wisdom, A. J.; Rogers, Z. J.; Chatterjee, F.; Cui, Y.; Garcia-Rivera, L.; Temple, H.; Abdelfattah, N. S.; Coombs, T.; Van, R.; Tafuri Del Vecchio, C.; So, H. K.; Heim, T.; Wolczanski, G.; Mount, C. W.; Butty, V.; Levine, S. S.; Cormier, K.; Love, J. C.; Kaech, S. M.; Jacks, T.; White, F.; Spranger, S.

doi:10.64898/2026.09.18.752741

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bioRxiv · 10.64898/2026.09.18.752741

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

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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.

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Wisdom, A. J., Rogers, Z. J., Chatterjee, F., Cui, Y., Garcia-Rivera, L., Temple, H., Abdelfattah, N. S., Coombs, T., Van, R., Tafuri Del Vecchio, C., So, H. K., Heim, T., Wolczanski, G., Mount, C. W., Butty, V., Levine, S. S., Cormier, K., Love, J. C., Kaech, S. M., Jacks, T., White, F., Spranger, S.. 2026-09-22. Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma. https://doi.org/10.64898/2026.09.18.752741

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