Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence

Hadeesha Piyadasa; Benjamin Oberlton; Mikaela Ribi; Ke Leow; Jolene S Ranek; Inna Averbukh; Meelad Amouzgar; Candace C Liu; Davide G Franchina; Noah F Greenwald; Erin F McCaffrey; Rashmi Kumar; Selena Ferrian; Albert G Tsai; Ferda Filiz; Christine Camacho Fullaway; Marc Bosse; Sricharan Reddy Varra; Alex Kong; Cameron Sowers; Melanie Hayden Gephart; Pablo Nuñez-Perez; EnJun Yang; Mike Travers; Michael J Schachter; Samantha Liang; Maria R Santi; Samantha Bucktrout; Pier Federico Gherardini; John Connolly; Kristina Cole; Michael E Barish; Christine E Brown; Derek A Oldridge; Richard R Drake; Joanna J Phillips; Hideho Okada; Robert Prins; Sean C Bendall; Michael Angelo

doi:10.1016/j.ccell.2025.11.006

Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence

Cancer Cell. 2026 Jan 12;44(1):112-128.e6. doi: 10.1016/j.ccell.2025.11.006. Epub 2025 Dec 11.

Authors

Hadeesha Piyadasa¹, Benjamin Oberlton², Mikaela Ribi³, Ke Leow⁴, Jolene S Ranek¹, Inna Averbukh¹, Meelad Amouzgar², Candace C Liu², Davide G Franchina¹, Noah F Greenwald⁴, Erin F McCaffrey¹, Rashmi Kumar¹, Selena Ferrian¹, Albert G Tsai¹, Ferda Filiz¹, Christine Camacho Fullaway¹, Marc Bosse¹, Sricharan Reddy Varra¹, Alex Kong¹, Cameron Sowers¹, Melanie Hayden Gephart⁵, Pablo Nuñez-Perez⁵, EnJun Yang⁶, Mike Travers⁶, Michael J Schachter⁶, Samantha Liang⁶, Maria R Santi⁷, Samantha Bucktrout⁶, Pier Federico Gherardini⁸, John Connolly⁶, Kristina Cole⁷, Michael E Barish⁹, Christine E Brown¹⁰, Derek A Oldridge¹¹, Richard R Drake¹², Joanna J Phillips¹³, Hideho Okada¹⁴, Robert Prins¹⁵, Sean C Bendall¹⁶, Michael Angelo¹⁷

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Immunology Program, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁷ Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
⁹ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
¹⁰ Departments of Hematology & Hematopoietic Cell Transplantation and Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
¹¹ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
¹³ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
¹⁴ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Neurosurgery, UCLA, Los Angeles, CA, USA.
¹⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Immunology Program, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Electronic address: bendall@stanford.edu.
¹⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Immunology Program, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Electronic address: mangelo0@stanford.edu.

PMID: 41386224
DOI: 10.1016/j.ccell.2025.11.006

Abstract

Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) landscape, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma, while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Paired samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206⁺ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study offers a framework for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.

Keywords: GBM; TME; diffuse midline glioma; glioma; immune regulation; immunotherapy; single-cell profiling; spatial N-glycome; spatial multi-omics; tumor antigens.

MeSH terms

Adult
Biomarkers, Tumor
Brain Neoplasms* / diagnosis
Brain Neoplasms* / genetics
Brain Neoplasms* / immunology
Brain Neoplasms* / pathology
Brain Neoplasms* / therapy
Child
Female
Gene Expression Profiling
Glioblastoma / genetics
Glioblastoma / pathology
Glioma* / diagnosis
Glioma* / genetics
Glioma* / immunology
Glioma* / pathology
Glioma* / therapy
Glycomics / methods
Humans
Isocitrate Dehydrogenase / genetics
Male
Middle Aged
Multiomics
Mutation
Neoplasm Recurrence, Local* / genetics
Neoplasm Recurrence, Local* / pathology
Proteomics / methods
Single-Cell Analysis
Transcriptome
Tumor Microenvironment / immunology

Substances

Isocitrate Dehydrogenase
Biomarkers, Tumor

Abstract

MeSH terms

Substances

Grants and funding