IGSF11-VISTA is a critical and targetable immune checkpoint axis in diffuse midline glioma

  • Cancer Cell. 2026 Mar 9;44(3):641-657.e9. doi: 10.1016/j.ccell.2025.12.020.
Raphaël Collot  1 ,  Cristian Ruiz-Moreno  2 ,  Celina Honhoff  1 ,  Thijs J M van den Broek  1 ,  Amber K L Wezenaar  1 ,  Daan J Kloosterman  1 ,  Hendrikus C R Ariese  1 ,  Hannah Johnson  1 ,  Britt M T Vervoort  1 ,  Amal Jeiroshi  3 ,  Jens Bunt  3 ,  Ravian L van Ineveld  1 ,  Emma Bokobza  1 ,  Heggert G Rebel  1 ,  Brigit M Te Pas  3 ,  Femke C A Ringnalda  1 ,  Marc van de Wetering  1 ,  Pierre A Robe  4 ,  Marcel Kool  5 ,  Jennifer R Cochran  6 ,  Mariëtte E G Kranendonk  3 ,  Dannis G van Vuurden  3 ,  Esther Hulleman  3 ,  Ellen J Wehrens  1 ,  Anoek Zomer  1 ,  Hendrik G Stunnenberg  2 ,  Anne C Rios  7
Affiliations
  • 1. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
  • 2. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, the Netherlands.
  • 3. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • 4. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 5. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; University Medical Center Utrecht, Utrecht, the Netherlands; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany.
  • 6. Department of Bioengineering, Stanford University Schools of Engineering and Medicine, Stanford, CA, USA.
  • 7. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 41576930 DOI: 10.1016/j.ccell.2025.12.020
Abstract

Diffuse midline Glioma (DMG) is an aggressive pediatric brain tumor with no curative treatment, and lacks a comprehensive understanding of immune-tumor cell interactions within their spatial context. Our multi-omics approach, integrating single-nuclei RNA Sequencing, spatial transcriptomics, and high-dimensional imaging, utilizes patient samples and an experimental murine DMG model to unveil two spatially distinct regions. MES-patterns are defined by mesenchymal (MES) tumor cells and blood-derived immune cells, whereas AOO-patterns are enriched with astrocyte (AC)-, oligodendrocyte (OC)-, and oligodendrocyte precursor cell (OPC)-like Cancer populations, alongside homeostatic-like microglia. The less-studied immune checkpoint, IGSF11, is primarily expressed by AOO-associated Cancer cells, while its receptor VISTA is detected mainly in homeostatic microglia. Targeting IGSF11-VISTA results in tumor reduction and survival benefit, mediated by brain-resident microglia and independent of T cell infiltration. This positions IGSF11-VISTA as a promising immune checkpoint treatment axis to harness the local brain immune response against DMG.

Keywords
IGSF11-VISTA immune checkpoint; cancer-immune landscape; diffuse midline glioma; microglia-cancer interaction; spatial multi-omics profiling.
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