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  • Review Article
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The promise of immunotherapy for central nervous system tumours

Nature Reviews Immunology volume 26, pages 213–229 (2026) Cite this article

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Abstract

The nervous and immune systems are intricately linked to one another through bi-directional crosstalk. Given the limited therapeutic options for aggressive and refractory central nervous system (CNS) tumours, immunotherapies are increasingly being explored as potential treatments for these malignancies. In this Review, we provide an overview of the nervous system–immune system connections that provide the basis for the use of immunotherapy to treat CNS tumours. We then summarize the outcomes from preclinical and clinical studies that have used immunotherapies, including chimeric antigen receptor T cell therapy, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors, for the treatment of primary CNS cancers such as high-grade gliomas, refractory embryonal brain tumours and primary CNS lymphomas. Finally, we review the neurological symptoms and syndromes that can arise with these immunotherapeutic approaches.

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Fig. 1: Immune cell trafficking at the brain border and potential factors limiting immunotherapy efficacy in the CNS.
The alternative text for this image may have been generated using AI.
Fig. 2: Main types of immunotherapy for central nervous system tumours.
The alternative text for this image may have been generated using AI.

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Acknowledgements

The authors are grateful for support from the Yuvaan Tiwari Foundation (M.M. and V.T.), the ChadTough Defeat DIPG Foundation (J.M. and M.M.), and the Chambers-Okamura Endowed Directorship for Paediatric Neuro-Immuno-Oncology (M.M.).

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Authors and Affiliations

  1. Division of Neurology and Developmental Neurosciences, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Jasia Mahdi

  2. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

    Vrunda Trivedi & Michelle Monje

  3. Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA

    Vrunda Trivedi & Michelle Monje

  4. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

    Michelle Monje

  5. Department of Pathology, Stanford University, Stanford, CA, USA

    Michelle Monje

  6. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Michelle Monje

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  1. Jasia Mahdi
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  2. Vrunda Trivedi
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The authors contributed equally to all aspects of the article.

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Correspondence to Michelle Monje.

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M.M. holds equity in CARGO Therapeutics and MapLight Therapeutics. The other authors declare no competing interests.

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Glossary

Anaplastic astrocytoma

These are grade III primary malignant brain tumours originating from astrocytes, a type of glial cell that supports the nervous system. The 2021 WHO classification of tumours has now removed the term anaplastic astrocytoma.

Antigen escape

This is an immune evasion mechanism in which the tumour cells downregulate or alter the expression of target antigens to avoid recognition by the immune system, particularly by the cytotoxic T lymphocytes.

Chimeric antigen receptor (CAR) T cells

These are genetically engineered T cells that express a synthetic receptor targeting surface antigens on cancer cells, enabling tumour recognition and destruction.

Convection-enhanced delivery

This is a targeted delivery method that infuses therapeutic agents directly into the brain, bypassing the blood–brain barrier and enhancing local distribution.

Co-stimulatory domains

These are intracellular signalling domains from T cell co-stimulatory molecules that are included in chimeric antigen receptor (CAR) constructs in order to optimize T cell activation.

Cytotoxic T lymphocytes

(CTLs). These are CD8+ T cells that can directly mediate cancer cell killing by releasing cytotoxic molecules such as granzymes and perforins.

Diffuse intrinsic pontine gliomas

(DIPGs). These are highly aggressive and diffusely infiltrative paediatric high-grade (WHO grade IV) gliomas arising in the pons and are characterized by often harbouring H3K27 alterations; they are associated with poor prognosis and resistance to conventional therapies. (DIPGs are a subset of diffuse midline gliomas).

Diffuse midline gliomas

(DMGs). These are aggressive and highly infiltrative high-grade gliomas (WHO grade IV) that arise in midline structures such as brainstem, thalamus and spinal cord, and are often characterized by H3K27 alterations.

Glioblastoma

(GBM). This is a highly aggressive (WHO grade IV) and infiltrative brain tumour characterized by a poor prognosis and is associated IDH wild-type, TERT promoter, chromosomes 7/10 and EGFR mutations. It is the most common type of primary malignant brain tumour in adults.

Immune escape mechanism

This is a mechanism that tumour cells use to evade immune detection by downregulating MHC class I molecules, thereby reducing antigen presentation and preventing cytotoxic T lymphocyte-mediated killing.

‘M1-like’ macrophages

‘M1’ and ‘M2’ are terms used to define macrophages activated in vitro as pro-inflammatory (when activated with interferon-γ and lipopolysaccharide) or anti-inflammatory (when alternatively activated with IL-4 or IL-10). In vivo, macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous. The M1 or M2 classifications are too simplistic to explain their true nature, but these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Medulloblastoma

These are malignant embryonal tumours that arise in the cerebellum and are the most commonly occurring malignant brain tumours in children; they are classified into distinct molecular subgroups with unique genetic and clinical characteristics.

Myeloid-derived suppressor cells

(MDSCs). These are immunosuppressive myeloid cells that inhibit T cell responses and are commonly associated with tumour progression and poor therapeutic outcomes in patients.

Oncolytic viruses

These are naturally occurring or genetically modified viruses that specifically infect, replicate within and kill the host cancer cells, thereby triggering an antitumour immune response.

Posterior fossa group A (PFA) ependymoma

These are rare and aggressive primary central nervous system tumours arising in the cerebellum that harbour mutations in H3K27me3 and EZHIP, and commonly affect children and young adults.

Tumour-infiltrating lymphocytes

(TILs). These are immune cells, more specifically T cells, that have migrated to the tumour microenvironment and are harnessed from the patient’s own tumour site. They are then engineered to recognize the cancer cells and induce tumour killing when infused back into the patient in conjunction with the T cell growth factor IL-2.

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Mahdi, J., Trivedi, V. & Monje, M. The promise of immunotherapy for central nervous system tumours. Nat Rev Immunol 26, 213–229 (2026). https://doi.org/10.1038/s41577-025-01227-5

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