The USP7-VIM axis mediates lipid metabolic remodelling and compromises CD8+ T-cell mitochondrial fitness in glioblastoma.

Glioblastoma (GBM) remains a highly lethal malignancy for which current treatments offer only a limited therapeutic benefit. Although vimentin (VIM) is classically regarded as a cytoskeletal protein, its role in tumour immune regulation is poorly understood. Here, we showed that extracellular tumour-derived VIM was associated with impaired CD8+ T-cell antitumour immunity and altered metabolic fitness. Single-cell RNA sequencing revealed that CD8+ T cells within VIM-high tumour microenvironments exhibited dysfunctional transcription in GBM. Functional assays revealed that VIM knockdown (VIM-KD) increased the antitumour activity of CD8+ T cells. Notably, under in vitro monoculture conditions, the modulation of VIM expression did not induce significant changes in GBM cell proliferation or apoptosis, indicating that VIM did not exert direct cytotoxic or growth-promoting effects on tumour cells. In contrast, in vivo tumour growth was strongly correlated with VIM expression levels, which was subsequently demonstrated to be mediated by CD8+ T-cell-dependent immune suppression. Metabolic analyses indicated that exposure to VIM-overexpressing (VIM-OE) tumour cells correlated with reduced triglyceride levels and decreased mitochondrial oxidative phosphorylation in CD8+ T cells. In vivo, VIM-KD mice exhibited decreased intracranial tumour growth and prolonged survival. Mechanistically, VIM stability is subject to posttranslational regulation, and we identified the deubiquitinase USP7 as a key regulator associated with maintaining VIM protein levels by limiting its proteasomal degradation. Collectively, these findings reveal a previously unrecognized USP7-VIM axis that mediates metabolic dysfunction and immune suppression in GBM, providing a mechanistic foundation for future therapeutic investigations.