Multimodal cell death-associated inflammatory niches recruit but spatially constrain GZMB+ cytotoxic T lymphocytes in glioblastoma.

BACKGROUND

GBM exhibits extensive necrosis and profound immune dysfunction, yet the role of multimodal cell death-associated inflammatory niches remains unclear.

METHODS

Bulk and single-cell transcriptomic datasets were integrated with spatial analyses and functional experiments to characterize these niches and evaluate stromal barriers and GZMB+ CTL activity.

RESULTS

Apoptosis, pyroptosis, and necroptosis markers formed spatial gradients toward necrotic tumor cores. These niches were associated with stemness, proliferation, epithelial-mesenchymal transition, p53 stress responses, and metabolic adaptation. Despite enhanced immune-recruiting signals and GZMB+ CTL accumulation, CTLs remained concentrated around necrotic and vascular regions rather than infiltrating tumor cell-dense areas. Extracellular matrix remodeling and CAF-like stromal barriers restricted CTL penetration and antitumor cytotoxicity.

CONCLUSIONS

Multimodal cell death-associated inflammatory niches paradoxically recruit GZMB+ CTLs while spatially constraining their function, revealing a potential mechanism linking necrosis to immune evasion and GBM progression.