Post-resection delivery of a TLR7/8 agonist from a biodegradable scaffold achieves immune-mediated glioblastoma clearance and protection against tumor challenge in mice
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.
Authors
- Kathryn M. Moore (ORCID: https://orcid.org/0000-0002-8483-1148)
- Ryan N. Woodring (ORCID: https://orcid.org/0000-0002-7818-8387)
- Garima Singh (ORCID: https://orcid.org/0000-0002-2198-0525)
- Eric M. Bachelder (ORCID: https://orcid.org/0000-0002-8572-888X)
- Sophie E. Mendell (ORCID: https://orcid.org/0000-0002-8700-1385)
- Aaron T. Hendricksen
- Peter E. Fecci (ORCID: https://orcid.org/0000-0002-2912-8695)
- Christopher J. Genito (ORCID: https://orcid.org/0000-0002-9044-964X)
- Sean R. Simpson (ORCID: https://orcid.org/0000-0003-0983-483X)
- Nicole Rose Lukesh (ORCID: https://orcid.org/0000-0003-4030-1505)
- Erik S. Pena (ORCID: https://orcid.org/0000-0002-9204-5155)
- Elizabeth G. Graham-Gurysh (ORCID: https://orcid.org/0000-0002-2130-5706)
- Kristy M. Ainslie (ORCID: https://orcid.org/0000-0002-1820-8382)
- Luis Ontiveros‐Padilla (ORCID: https://orcid.org/0000-0002-7705-9989)
- William C. Zamboni (ORCID: https://orcid.org/0000-0002-8319-4482)
- Shawn Hingtgen (ORCID: https://orcid.org/0000-0003-4355-2377)
- A. López
- Connor T. Murphy (ORCID: https://orcid.org/0009-0009-2533-5804)
- Grace L. Williamson (ORCID: https://orcid.org/0000-0003-4711-1130)
- Kaitlyn A. Hipp
Institutions
- University of North Carolina at Chapel Hill (US)
- University of North Carolina Health Care (US)
- North Carolina State University (US)
- Duke Medical Center (US)
- Duke University Hospital (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41467-025-63692-9
- Citations
- 1
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- National Science Foundation
- National Institutes of Health
- Center for AIDS Research, University of Washington
- University of North Carolina at Chapel Hill
- Division of Electrical, Communications and Cyber Systems
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill