Watson, Spencer S., Zomer, Anoek, Fornier, Nadine, Lourenco, Joao, Nassiri, Sina, Quadroni, Mandredo, Aubel, Pauline, Broekman, Merike L. D., Huse, Jason T., Hottinger, Andreas F., Cossu, Giulia, Daniel, Roy T., Hegi, Monika E. and Joyce, Johanna A. (2024) Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence. Cancer cell, 42 (9). 1507-1527.e11. ISSN 1878-3686

Abstract

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.

Item Type:	Article
Keywords:	Glioblastoma Animals Humans Mice Neoplasm Recurrence, Local Tumor Microenvironment Fibrosis Brain Neoplasms Receptor, Macrophage Colony-Stimulating Factor Cell Line, Tumor Signal Transduction Xenograft Model Antitumor Assays Transforming Growth Factor beta
Date Deposited:	05 Mar 2026 00:45
Last Modified:	05 Mar 2026 00:45
URI:	https://oak.novartis.com/id/eprint/50722