Targeting immunosuppressive myeloid cells via implant-mediated slow release of small molecules to prevent glioblastoma recurrence

  • Nat Biomed Eng. 2025 Oct 22. doi: 10.1038/s41551-025-01533-2.
Yannik Kaiser  1 ,  Christopher S Garris  1  2 ,  Eliana Marinari  3  4  5  6 ,  Hyung Shik Kim  1 ,  Juhyun Oh  1 ,  Martin Pedard  3  4  5  6 ,  Elias A Halabi  1 ,  Moonhyun Choi  1 ,  Sepideh Parvanian  1 ,  Rainer Kohler  1 ,  Denis Migliorini  3  4  5  6 ,  Ralph Weissleder  7  8
Affiliations
  • 1. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
  • 2. Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Oncology, University Hospital of Geneva, Geneva, Switzerland.
  • 4. Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.
  • 5. Brain Tumor and Immune Cell Engineering Laboratory, AGORA Cancer Research Center, Lausanne, Switzerland.
  • 6. Swiss Cancer Center Léman (SCCL), Geneva, Switzerland.
  • 7. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. [email protected].
  • 8. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 41125869 DOI: 10.1038/s41551-025-01533-2
Abstract

Glioblastoma is a highly aggressive brain tumour with a high risk of recurrence after surgery, even when combined with chemotherapy and radiotherapy. A major barrier to lasting treatment is the tumour's immunosuppressive environment, which is largely dominated by myeloid cells. Here we describe the development of a biodegradable implant to sustainably release immune-modulator small molecules to reprogram tumour-infiltrating myeloid cells toward a pro-inflammatory, antitumour phenotype in the surgical cavity after tumour removal. In immunocompetent mouse models, this therapy induces interleukin-12 expression in myeloid cells without systemic cytokine elevation, and increases the infiltration of CD8+ and CD4+ T cells. Over 50% of mice treated (in combination with radiotherapy and chemotherapy) remain tumour-free during the experimental course (80 days). We further treated human glioblastoma explants ex vivo with the therapy and observed increased interleukin-12 expression in tumour-infiltrating myeloid cells, supporting the translational potential of this strategy. This implantable system offers a promising approach to prevent glioblastoma recurrence by activating innate immunity and sustaining immune surveillance post-surgery.

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