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Previous work shows that a small population of quiescent SOX2⁺ medulloblastoma (MB) stem cells can drive tumour growth in early tumorigenesis and relapse. Here, the authors identify OLIG2 as a transcriptional mediator of the transition from quiescent to rapidly proliferating progenitor states and therapeutically target this axis in preclinical models of MB.

Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

The oncolytic virus Delta-24-RGD is in clinical trial for adult glioma. Here, the authors show that this virus elicits an immune response in mouse models of pediatric high-grade glioma and diffuse pontine intrinsic glioma, resulting in improved survival.

Bioprinting has potential in the biofabrication of three dimensional tissues, but is poorly suited to the manipulation of neural organoids. Here, the authors develop a bioprinting platform to allow the arrangement of organoids to form assembloids.

Over the past decade, multiple lines of inquiry have converged on the appreciation that the nervous system plays crucial roles in cancer pathophysiology. Key conceptual advances will mark 2025 as a milestone year in which the ‘emerging’ cancer neuroscience field developed into an established field. Here, we discuss the latest developments.

We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M⁺ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

A phase I dose-escalation trial of GD2-CAR T cells in children and young adults with diffuse midline gliomas to assess the feasibility of manufacturing, safety and tolerability, and to preliminarily assess efficacy.

Callosal projection neurons located in the hemisphere contralateral to primary glioblastoma promote progression and widespread infiltration, and screening of axon guidance genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression.

CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.

Mouse models of NF1-associated optic pathway glioma show that tumour initiation and growth are driven by aberrantly high levels of NLGN3 shedding in the optic nerve in response to retinal neuron activity.

The combination of anti-GD2 and CD47 blockade mediates robust anti-tumor activity in mouse models of neuroblastoma, osteosarcoma and small-cell lung cancer by reorienting macrophage activity toward tumor cell phagocytosis.

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.

Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity drives proliferation of small lung cell cancer via paracrine interactions and through synapses formed with tumour cells.

Functional, tumour-promoting GABAergic neuron-to-glioma synapses in diffuse midline gliomas are identified.

A neural epigenetic signature detectable via plasma analyses is prognostic in patients with glioblastoma, resembling an oligodendrocyte-progenitor- and neuronal-progenitor-cell-like state and showing increased neuro-to-glioma synapse formation.

Oligodendrogenesis is shown to be involved in reward learning, with dopaminergic neuronal activity-regulated myelin plasticity being an important reward circuit modification.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

Activity-dependent oligodendroglial plasticity contributes to neuronal functions. Here the authors show that adaptive oligodendrocyte progenitor cell responses are disrupted in neurofibromatosis 1, impairing oligodendroglial dynamics and resulting in motor learning deficits in Nf1-deficient and Nf1-mutant mice.

Mabe et al. find that GD2 levels correlate with lineage plasticity in neuroblastoma and identify ST8SIA1 as the key enzyme in GD2 synthesis. EZH2 inhibition in mesenchymal neuroblastoma cells elevates ST8SIA1, synergizing with anti-GD2 antibodies.

Neuron–oligodendroglial interactions modulate neural circuit structure and function in the healthy brain. In this Review, Taylor and Monje describe the accumulating evidence for how glial malignancies subvert and repurpose these powerful neuron–glial interactions to drive glioma pathophysiology.

In glioma, malignant synapses hijack mechanisms of synaptic plasticity to increase glutamate-dependent currents in tumour cells and the formation of neuron–glioma synapses, thereby promoting tumour proliferation and progression.

Individuals with long COVID show marked biological changes in cortisol and immune factors relative to convalescent populations.

High-grade gliomas functionally remodel neural circuits in the human brain, promoting tumour progression and impairing cognition.

This Review explains how an improved understanding of immune and nervous system interactions in the central nervous system (CNS) has guided the use of immunotherapies (including chimeric antigen receptor T cells, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors) to treat CNS tumours. The authors highlight the outcomes of clinical trials that have used immunotherapy to treat primary brain cancers and provide a perspective on future directions for the field.

Recurrent absence seizures aberrantly increase activity-regulated myelination within the seizure network; this maladaptive myelination, in turn, increases network hypersynchrony and seizure burden over time.

Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that Nf1 mutations differentially drive both central and peripheral nervous system tumor growth in mice through reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function.

Neurons form synapses onto glioma cells, and depolarization of glioma membranes promotes glioma growth in vivo, whereas blocking electrochemical signalling blocks tumour growth.

Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models.

Genomic and functional analysis of intratumor heterogeneity in pediatric glioma uncovers early clonal divergence and stable spontaneous cooperation between subclonal populations throughout tumor evolution.

The nervous system can drive the initiation, growth, spread, and therapy resistance of cancer, and cancer can manipulate the nervous system in ways that further support disease progression. Tumors growing within the brain or elsewhere in the body connect with neuronal networks in circuit-specific manners, via neuron-to-cancer synaptic interactions and paracrine crosstalk. Moreover, neural factors govern critical components of the tumor environment, such as the immune system, and cancer can use neural mechanisms in a malignant cell-intrinsic manner. Here we provide a personal view on the burgeoning field of cancer neuroscience and highlight the need to approach cancer research from a neuroscience perspective — together with neuroscientists.

The study describes the use of integrative approaches to search for candidate therapeutic targets for DIPG, and the identification of an HDAC inhibitor as a potential treatment strategy

Metformin can promote the regeneration of neural precursor cell populations and improve cognitive function in a preclinical model of cranial radiation and a pilot clinical study of children after cranial radiation and chemotherapy.

Cancers dependent on hedgehog pathway signaling are susceptible to the BET bromodomain inhibitor JQ1.

Diffuse intrinsic pontine glioma (DIPG) is an almost incurable malignant childhood brain tumor. Here, the authors show that the polyamine synthetic pathway is activated in DIPG and that the dual targeting of polyamine synthesis and uptake results in prolonged survival in animal models.

Chris Jones, Jacques Grill and colleagues report the identification of recurrent activating mutations in ACVR1 in diffuse intrinsic pontine gliomas.

Optical microscopy allows neural cells to be studied in the intact brain, but imaging deep neural tissue presents substantial challenges. Prevedel and colleagues outline the principles of three-photon microscopy, highlighting its advantages for deep tissue imaging and its applications in neuroscience.

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Lethal pediatric tumors bearing a particular histone H3 mutation upregulate the disialoganglioside GD2, thereby making these tumors susceptible to chimeric antigen receptor T cell–based immunotherapy.

The growth of adult and paediatric brain tumours depends on a microenvironmental signalling pathway involving the activity-regulated secretion of neuroligin-3 (NLGN3) from normal neurons and oligodendrocyte precursor cells, highlighting the potential of NLGN3 as a therapeutic target.

Single-cell or single-nucleus RNA-sequencing experiments form a basis for biological insights about cell types and states, but they require orthogonal experiments to confirm the functional relevance of their findings. Here the authors discuss options to support such findings and their challenges.

The authors describe a localized toxicity syndrome that is associated with immunotherapy treatment for CNS tumors and propose a new grading scale—with the goal of promoting research and standardizing both reporting and management.

In this Review, the authors provide an overview of evidence that activity-regulated myelination is required for brain adaptation and learning, and discuss how dysregulation of activity-dependent myelination contributes to neurological disease and could be a new therapeutic target.

This Primer by Weller and colleagues summarizes the epidemiology, pathophysiology, diagnosis and treatment of glioma in both adults and children.

This Review examines the interplay between the nervous system and tumours, from cancer initiation to progression and metastasis.

Childhood cancers are developmentally distinct from adult cancers and arise from cellular reprogramming as a result of epigenetic mutations or gene fusions, providing unique therapeutic opportunities.

Diana Carvalho, Kathryn R. Taylor et al. show that ALK2 inhibitors induce apoptosis of ACVR1 mutant diffuse intrinsic pontine glioma cells in vitro. These compounds also increase the survival of mice carrying ACVR1 mutant brainstem xenografts, suggesting ALK2 as a potential pharmacological target against this lethal cancer.