GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE294nnn/GSE294939/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294939GEOGSEfalseDecoding Plasticity Regulators and Transition Trajectories in Glioblastoma with Single-cell Multiomics [RNA-seq]Glioblastoma (GB) is incurable and resistant to therapy despite genomic stability under treatment, implicating non-genetic cellular plasticity as a central driver of progression. Whether such plasticity reflects stochastic state switching or is governed by predictable gene regulation has remained unresolved. We applied scDORI, a deep-learning framework that infers enhancer-driven gene regulatory networks at single cell resolution, to single-nucleus multi-ome profiles of over one million cells from primary GBs. Integrating computational inference with systematic gain-of-function screens across patient-derived models, we show that GB cellular plasticity is governed by a structured regulatory program with an asymmetric interplay of activators and repressors. The resulting transition landscape is hierarchical and predictable, yet permits cross-lineage trajectories absent from normal neurodevelopment. Within this landscape, low-plasticity states such as the Neuronal-like state are not stable differentiation endpoints but actively maintained configurations, stabilized by a network of safeguard repressors that silence alternate fates. MYT1L emerged as the dominant member of this network, binding and repressing master regulators of every alternative state to consolidate Neuronal-like identity. MYT1L restricted plasticity even under standard-of-care therapy and suppressed tumor growth and invasion in vivo. Conversely, MYT1L loss reactivated plasticity and accelerated malignant features, demonstrating that low-plasticity identity requires continuous repression. These findings reframe malignant cell state stability as a balance between activation and continuous repression, and nominate safeguard repressors as candidate therapeutic targets distinct from differentiation-inducing activators, with potential relevance across cancers in which phenotypic switching drives therapy resistance.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 sapiens