Programs, origins and immunomodulatory functions of myeloid cells in glioma

Tyler E. Miller, Chadi A. El Farran, Charles P. Couturier, Zeyu Chen, Joshua P. D’Antonio, Julia Verga, Martin A. Villanueva, L. Nicolas Gonzalez Castro, Yuzhou Evelyn Tong, Tariq Al Saadi, Andrew N. Chiocca, Yuanyuan Zhang, David S. Fischer, Dieter Henrik Heiland, Jennifer L. Guerriero, Kevin Petrecca, Mario L. Suva, Alex K. Shalek and Bradley E. Bernstein ()
Additional contact information
Tyler E. Miller: Dana Farber Cancer Institute
Chadi A. El Farran: Dana Farber Cancer Institute
Charles P. Couturier: Dana Farber Cancer Institute
Zeyu Chen: Dana Farber Cancer Institute
Joshua P. D’Antonio: Dana Farber Cancer Institute
Julia Verga: Dana Farber Cancer Institute
Martin A. Villanueva: Broad Institute of MIT and Harvard
L. Nicolas Gonzalez Castro: Broad Institute of MIT and Harvard
Yuzhou Evelyn Tong: Broad Institute of MIT and Harvard
Tariq Al Saadi: McGill University
Andrew N. Chiocca: Dana Farber Cancer Institute
Yuanyuan Zhang: Dana Farber Cancer Institute
David S. Fischer: Broad Institute of MIT and Harvard
Dieter Henrik Heiland: Medical Center - University of Freiburg
Jennifer L. Guerriero: Ludwig Center at Harvard Medical School
Kevin Petrecca: McGill University
Mario L. Suva: Broad Institute of MIT and Harvard
Alex K. Shalek: Broad Institute of MIT and Harvard
Bradley E. Bernstein: Dana Farber Cancer Institute

Nature, 2025, vol. 640, issue 8060, 1072-1082

Abstract: Abstract Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined1. Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems. We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours. The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1β, TGFβ and standard-of-care dexamethasone treatment. Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies.

Date: 2025
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DOI: 10.1038/s41586-025-08633-8

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