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Agnihotri and colleagues show that loss of the MAT2A enzyme of the methionine cycle induces a global depletion of H3K36me3 and extends survival in glioma models, representing a potential therapeutic vulnerability.

Histone H3-mutant gliomas are deadly brain tumours and the tumour microenvironment is not fully understood. Here the authors profile the immune microenvironment from human samples and mouse models and implicate myeloid cells in immune suppression and show inhibition of myeloid cells and checkpoint blockade demonstrates therapeutic benefits in mice.

The molecular mechanisms underlying the function of different cellular states in glioblastoma stem cells (GSCs) remain poorly understood. Here, the authors perform integrated single cell and bulk analysis of GSCs and identify potential therapeutic targets.

Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma.

Radiation-induced meningiomas are often more aggressive than sporadic ones. In this study, the authors perform an exome, methylation and RNA-seq analysis of 31 cases of radiation-induced meningioma and show NF2 rearrangement, an observation previously unreported in the sporadic tumors.

Zou et al. show that SMARCD3 regulates DAB1 activity and Reelin signalling in the developing cerebellum, which can be hijacked to promote medulloblastoma cell migration and metastatic dissemination.

Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.

Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.

The metabolism of temozolomide (TMZ) to form methyldiazonium ions and 5-aminoimidazole-4-carboxamide (AICA) results in DNA damage, despite this, resistance frequently occurs in glioblastoma. Here, the authors demonstrate that AICA is further metabolised by HPRT1 into AICAR, which activates AMPK signalling and increases DNA damage repair. Targeting this axis in preclinical glioblastoma models sensitised tumours to TMZ.

A risk score based on a 34-gene signature for outcome prediction in meningioma was developed and validated in large multi-institutional cohorts and showed better performance in discriminating postoperative menignioma outcomes compared with existing meningioma classification systems.

GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder.

Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.

Single-cell RNA-seq and ATAC-seq, combined with spatial transcriptomics, identify age- and location-related cellular dynamics of diffuse midline gliomas, such as variable oligodendrocyte precursor-like tumor stem cell populations and increased mesenchymal states with age.

With non-small cell lung cancer (NSCLC) being the leading cause of cancer deaths worldwide, the development of targeted therapies remains crucial. Here, the generation and multi-omics characterization of 137 NSCLC patient-derived xenografts provides a resource for potential classifications and targets.

Capicua (CIC) is a tumour suppressor in oligodendroglioma. Here, the authors show that ERK activation mediates CIC regulation via ubiquitination and degradation by PJA1 and a degradation resistant form of CIC enhances efficacy of ERK inhibition in glioblastoma.

Gelareh Zadeh, Kenneth Aldape and colleagues present an integrative genomic analysis of schwannomas. In addition to finding recurrent mutations in ARID1A, ARID1B and DDR1, they identify a recurrent SH3PXD2A-HTRA1 fusion that confers increased proliferation, invasion and in vivo transformation, and is associated with sensitivity to MEK inhibition.

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous.

Cynthia Hawkins, Oren Becher and colleagues report the identification of recurrent mutations in ACVR1 in 20% of diffuse intrinsic pontine gliomas.

This Review discusses molecular circuitry underlying adaptive plasticity in brain cancer stem cells, highlighting the transcriptional classification of the stem cell state, neoplastic evolution and development of therapeutic resilience, and critical brain-specific microenvironmental inputs with the goal of informing next-generation stem-targeted treatment paradigms.