2. Academic Validation
  3. IGSF11-VISTA is a critical and targetable immune checkpoint axis in diffuse midline glioma

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

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.

Figures
Products