Post-resection delivery of a TLR7/8 agonist from a biodegradable scaffold achieves immune-mediated glioblastoma clearance and protection against tumor challenge in mice

Elizabeth G. Graham-Gurysh, Ryan N. Woodring, Sean R. Simpson, Sophie E. Mendell, Nicole Rose Lukesh, Erik S. Pena, Kathryn M. Moore, Luis A. Ontiveros-Padilla, Aaron T. Hendricksen, Alexandra M. Lopez, Grace L. Williamson, Connor T. Murphy, Christopher J. Genito, Kaitlyn A. Hipp, Garima Singh, William C. Zamboni, Shawn D. Hingtgen, Peter E. Fecci, Eric M. Bachelder and Kristy M. Ainslie ()
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Elizabeth G. Graham-Gurysh: University of North Carolina at Chapel Hill
Ryan N. Woodring: University of North Carolina at Chapel Hill
Sean R. Simpson: University of North Carolina at Chapel Hill
Sophie E. Mendell: University of North Carolina at Chapel Hill
Nicole Rose Lukesh: University of North Carolina at Chapel Hill
Erik S. Pena: University of North Carolina at Chapel Hill and North Carolina State University
Kathryn M. Moore: University of North Carolina at Chapel Hill and North Carolina State University
Luis A. Ontiveros-Padilla: University of North Carolina at Chapel Hill
Aaron T. Hendricksen: University of North Carolina at Chapel Hill
Alexandra M. Lopez: University of North Carolina at Chapel Hill
Grace L. Williamson: University of North Carolina at Chapel Hill
Connor T. Murphy: University of North Carolina at Chapel Hill
Christopher J. Genito: University of North Carolina at Chapel Hill
Kaitlyn A. Hipp: University of North Carolina at Chapel Hill
Garima Singh: University of North Carolina at Chapel Hill
William C. Zamboni: University of North Carolina at Chapel Hill
Shawn D. Hingtgen: University of North Carolina at Chapel Hill
Peter E. Fecci: Duke University Medical Center
Eric M. Bachelder: University of North Carolina at Chapel Hill
Kristy M. Ainslie: University of North Carolina at Chapel Hill

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Glioblastoma is an aggressive brain cancer with a dismal prognosis despite current therapeutic interventions. Surgical tumor resection, standard-of-care for glioblastoma, not only results in the reduction of tumor burden, but also has profound immunostimulatory effects, offering a unique opportunity to break local immune tolerance and mount an effective anti-tumor immune response. Here, we explore the effect of local controlled release of resiquimod, a TLR7/8 agonist, from a biodegradable polymer scaffold implanted at the time of tumor resection. We find that treatment leads to the clearance of residual post-resection tumor, improved survival, and subsequent protection from tumor challenges in orthotopic mouse models of glioma. In addition, the controlled release of resiquimod from the scaffold boosts the resection-mediated disruption to the tumor microenvironment, leading to an early inflammatory innate immune response both in the brain and cervical lymph node, followed by an influx of lymphocytes. Thus, we show that sustained local TLR7/8 agonism at the time of tumor resection represents a promising approach for the treatment of glioblastoma.

Date: 2025
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DOI: 10.1038/s41467-025-63692-9

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