biostudies-literatureClements MNCI NIH HHSWellcome Trust452-461https://www.ebi.ac.uk/biostudies/studies/S-EPMC12507684biostudies-literatureUnknown646(8084)Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour^1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death³, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration⁴, was sufficient to breNatureAxonal injury is a targetable driver of glioblastoma progression.PMC12507684R35 CA242447218278/Z/19/ZKaramched SRCastro Devesa SShahrezaei VFlorjanic Baronik ZRoncaroli FSugisawa RMarguerat SLindsay ROria RUddin ISimpson Ragdale HVolteras DWeaver VMParrinello SWhite IJClements MLythgoe MFTang WBeattie GLenn THill CSfalseAxonal injury is a targetable driver of glioblastoma progression.Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour^1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death³, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration⁴, was sufficient to bre2025-01-01T00:00:00Z2025 Oct2026-06-06T13:57:54.929Z2026-05-31T03:10:14.323ZS-EPMC125076844083608110.1038/s41586-025-09411-2