In situ single-cell CRISPR screens uncover context-dependent rewiring of glioma states and immune recruitment

Loss of NF1 in RCAS-TVA glioma initiation yields genotype-dependent transcriptional states, including increased mesenchymal programs, and fixed Cdkn2a(ARF) perturbation rewires malignant and immune composition.

• Why it matters: In vivo single-cell CRISPR screens rarely integrate cell-type-restricted delivery with somatic tumor initiation and combinatorial perturbations, limiting insight into how context reshapes tumor states and immune recruitment.
• What they did: The authors built an RCAS-TVA single-cell CRISPR screening workflow in defined neural progenitors, using single- or dual-guide perturbations during in vivo tumor initiation, then profiled transcriptional states and immune abundance.
• The result: Cdkn2a(ARF) perturbation shifts malignant-state composition and immune-cell abundance and increases representation of Pten- and Rb1-deficient cells, aligning with transcriptional states resembling pharmacologic p53 activation and linking to increased astrocyte-like representation across mouse tumors and human glioblastoma models.

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