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Therapeutic approaches for targeting the pediatric brain tumor microenvironment

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Abstract

Central nervous system (CNS) tumors are the most frequent solid malignant tumors in pediatric patients and are the leading cause of tumor-related death in children. Treatment for this heterogeneous group of tumors consists of various combinations of safe maximal surgical resection, chemotherapy, and radiation therapy which offer a cure for some children but often cause debilitating adverse late effects in others. While therapies targeting the tumor microenvironment (TME) like immune checkpoint inhibition (ICI) have been successful in treating some cancers, these therapies failed to exhibit treatment efficacy in the majority of pediatric brain tumors in the clinic. Importantly, the pediatric TME is unique and distinct from adult brain tumors and designing therapies to effectively target these tumors requires understanding the unique biology of pediatric brain tumors and the use of translational models that recapitulate the TME. Here we describe the TME of medulloblastoma (MB) and diffuse midline glioma (DMG), specifically diffuse intrinsic pontine glioma (DIPG), and further present the current drug delivery approaches and clinical administration routes targeting the TME in these tumors, including preclinical and clinical studies.

Graphical Abstract

Considerations for developing therapeutic approaches to target pediatric brain tumor microenvironment including drug delivery carriers, CNS specific delivery routes, and clinically relevant models for preclinical evaluation 1.

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Acknowledgements

The authors would like to thank Dr. Leaf Huang for his mentorship and feedback on the early stages of this article. Figures were created in Biorender.

Funding

This work was supported by National Institutes of Health T32 funding from the Program in Translational Medicine at the University of North Carolina at Chapel Hill (NIH T32GM122741), National Center for Advancing Translational Sciences (K12TR004416), National Institutes of Health (U01TR003715), and by the Isabella Santos Foundation TORCH Initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.

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Authors and Affiliations

  1. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Caroline A. Stockwell, Andrew B. Satterlee & Shawn Hingtgen

  2. Eshelman Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Andrew B. Satterlee

  3. Division of Pediatric Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    David E. Kram

  4. Neuroscience Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Morrent Thang

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All authors contributed to the conceptualization of this work. The first draft of the manuscript was written by C.A.S. and all authors contributed to the writing and revision process. All authors approved the final manuscript.

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Correspondence to Shawn Hingtgen.

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We affirm that our manuscript has not been submitted for publication elsewhere, and there are no undeclared competing financial interest. S.H., and A.B.S. have submitted a patent application based on the OBSC platform mentioned in this work. C.A.S, M.T. and D.E.K declare no competing interest.

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Stockwell, C.A., Thang, M., Kram, D.E. et al. Therapeutic approaches for targeting the pediatric brain tumor microenvironment. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01839-3

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