Single-cell and spatial transcriptomics dissect the prognosis and vascular association of a disulfidptosis gene-set score in glioblastoma

Purpose. Disulfidptosis is a glucose-starvation-induced regulated cell death, but its prognostic and microenvironmental relevance in glioblastoma (GBM) is unknown. We therefore enumerated the complete disulfidptosis gene pool, defined a prognostic gene-set score (DSscore), and resolved its molecular, immune and cell-type/spatial associations in public bulk, single-cell and spatial data. Methods. From all publicly accessible, non-lncRNA disulfidptosis genes (38-gene pool, 100% measurable), univariate Cox regression in the CGGA discovery cohort (n = 693) identified 27 prognostic genes, and each sample was scored by single-sample gene-set enrichment analysis against the full transcriptome (DSscore). Prognostic value was validated in four independent cohorts and adjusted for clinical and molecular covariates. Molecular-class, immune-infiltration and hallmark associations were assessed, and the spatial cell-type association was examined by single-cell and RCTD-deconvolved spatial transcriptomics, with a discriminant-validity analysis. Results. High DSscore predicted worse survival in CGGA (median OS 470 versus 2982 days; log-rank P < 0.001) and remained independent after adjustment for age, WHO grade, recurrence and IDH status (HR 2.31, 95% CI 1.75–3.04). The direction was consistent across four independent cohorts (pooled HR 1.50, 95% CI 1.19–1.90; I² = 4%). DSscore was higher in IDH-wildtype, non-1p19q-codeleted and grade-IV tumors and correlated with immune infiltration and with interferon/inflammatory/EMT hallmark programs. Across four Visium slices (11,126 spots), DSscore was enriched in the vascular-lymphangioblast (endothelial) niche, and single-cell analysis showed the highest DSscore in vascular lymphangioblasts, which expressed the disulfidptosis gate SLC7A11/SLC3A2. Conclusions. DSscore marks an immune-infiltrated, high-grade GBM state with independent prognostic value and a vascular-associated spatial profile.