NF1 Leucine Rich Domain-Derived Extracellular Vesicles Remodel the Glioblastoma Immune Microenvironment via an ADAM17-Associated Inflammatory Program.

Authors

Yuganthini Vijayanathan, Jacqueline Yt Yeo, Janice Hy Tan, Fikri Bin Mohamed, Bernett Lee, Tatsuya Kozaki, Nurashikin Abdul Halim, Rachel Ly Ho, Hai Tao Tu, Zhi Wei Zhang, Jann N Sarkaria, Li Zeng, Florent Ginhoux, Ivy Aw Ho

Published in

Journal of extracellular vesicles. Volume 15. Issue 8. Pages e70355.

Abstract

Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in cancer. We previously demonstrated that re-expression of the leucine-rich domain (LRD) of neurofibromin (NF1) suppresses glioblastoma (GBM) invasion and limits microglia/macrophage infiltration into the tumor microenvironment (TME). Given the central role of tumor-associated microglia/macrophages (TAMs) in GBM progression, we investigated whether NF1-LRD-containing EVs (NF1-LRD-EVs) could modulate TAM function and remodel the TME. Our results showed that NF1-LRD-EVs attenuated microglia and macrophage recruitment in migration assays, consistent with reduced microglia/macrophage recruitment observed in vivo. In parallel, treatment with NF1-LRD-EVs enhanced phagocytic activity of both microglia and iPSC-derived macrophages, accompanied by induction of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and downregulation of immunosuppressive mediators such as Arginase-1 and IL-10. Mechanistically, NF1-LRD-EVs induced ADAM17-associated inflammatory signaling, accompanied by NF-κB activation. Pharmacological inhibition of ADAM17 reduced TNF-α release and attenuated NF-κB activation, supporting a role for ADAM17-dependent signaling in amplifying this inflammatory response. Together, these findings show that NF1-LRD-EVs reprogram TAMs toward a pro-inflammatory phenotype and modulate the GBM immune microenvironment. These results provide a framework for understanding NF1-LRD-EV-mediated immune regulation and support further investigation of EV-mediated immune modulation of the TME.

PMID:
42627929
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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