Peer-reviewedCC BYNature
Dual tumour–myeloid targeting of glioblastoma with GPNMB CAR-T cells
16 affiliations
- 1Centre for Discovery in Cancer Research, McMaster University, Hamilton, Ontario, Canada
- 2Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- 3Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
- 4Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- 5Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- 6Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- 7Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
- 8Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- 9McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- 10Division of Neurosurgery, Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
- 11Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- 12Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada
- 13Centre for Discovery in Cancer Research, McMaster University, Hamilton, Ontario, Canada. [email protected]
- 14Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. [email protected]
- 15Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. [email protected]
- 16School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, King's College London, London, UK. [email protected]
Abstract
Glioblastoma is a lethal brain tumour for which current multimodal treatment rarely prevents recurrence 1 . Therapeutic failure is driven by extensive intratumoural cellular heterogeneity 2 with a microenvironment dominated by tumour-associated macrophages that sustain tumour growth and immunosuppression 3 . Although chimeric antigen receptor (CAR)-T cell therapies are being developed for glioblastoma, sustained response has been undermined by non-uniform antigen expression, antigen loss and microenvironmental barriers that are not directly engaged by tumour-targeting designs 4 . These limitations motivate new strategies that address the disease as a coupled tumour–immune system rather than a single malignant compartment. Here we use a multi-omic target discovery platform to identify GPNMB as a dual-compartment antigen in glioblastoma. Anti-GPNMB CAR-T cells showed potent anti-tumour activity, with long-term disease control in orthotopic patient-derived xenografts and syngeneic glioma models through concomitant depletion of GPNMB + tumour and immunosuppressive myeloid populations. By collapsing tumour control and microenvironmental reprogramming, these findings provide a new strategy for antigen selection and targeting in heterogenous, myeloid-rich solid cancers.
Related
- 68 Translational PET imaging of suppressive granulocytic myeloid cells in glioblastoma
- Discovery of compounds targeting human acute myeloid leukemia stem cells via a novel high-throughput screen
- AI-driven discovery of GPNMB CAR T cells as a multi-cancer therapy
- CLEC10A marks an MHC class II-high tumour myeloid state that lies in T-cell-rich neighbourhoods, and its survival association is seen in MYCN non-amplified neuroblastoma
- Therapeutic Targeting of the TGFβ Pathway Augments CAR T cell Efficacy in Glioblastoma
BibTeX
@article{savage2026dual,
title = {{Dual tumour–myeloid targeting of glioblastoma with GPNMB CAR-T cells}},
author = {Neil J. Savage and Shan Grewal and Muhammad Vaseem Shaikh and Franz J. Zemp and Dillon McKenna and Nicholas Mikolajewicz and Hinda Najem and Joanna Pyczek and Jiuran Wei and Mohamed Taleb and Lucas C. Asselstine and Alisha Anand and Shawn C. Chafe and Kui Zhai and William T. Maich and Chirayu Chokshi and Hardikkumar Patel and Tiegan Korman and Minomi Subapanditha and Zoya Tabunshchyk and Nazanin Tatari and Petar Miletic and Di Chen and Sebastián Pacheco and Abdelsimar Tan Omar and Bo Wang and 韩红 and Jennifer Ai-wen Chan and Kevin R. Brown and Chitra Venugopal and Thomas Kislinger and Amy B. Heimberger and Jason Moffat and Douglas J. Mahoney and Sheila Kumari Singh},
journal = {Nature},
year = {2026},
month = jul,
doi = {10.1038/s41586-026-10641-1},
url = {https://doi.org/10.1038/s41586-026-10641-1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dual tumour–myeloid targeting of glioblastoma with GPNMB CAR-T cells
AU - Neil J. Savage
AU - Shan Grewal
AU - Muhammad Vaseem Shaikh
AU - Franz J. Zemp
AU - Dillon McKenna
AU - Nicholas Mikolajewicz
AU - Hinda Najem
AU - Joanna Pyczek
AU - Jiuran Wei
AU - Mohamed Taleb
AU - Lucas C. Asselstine
AU - Alisha Anand
AU - Shawn C. Chafe
AU - Kui Zhai
AU - William T. Maich
AU - Chirayu Chokshi
AU - Hardikkumar Patel
AU - Tiegan Korman
AU - Minomi Subapanditha
AU - Zoya Tabunshchyk
AU - Nazanin Tatari
AU - Petar Miletic
AU - Di Chen
AU - Sebastián Pacheco
AU - Abdelsimar Tan Omar
AU - Bo Wang
AU - 韩红
AU - Jennifer Ai-wen Chan
AU - Kevin R. Brown
AU - Chitra Venugopal
AU - Thomas Kislinger
AU - Amy B. Heimberger
AU - Jason Moffat
AU - Douglas J. Mahoney
AU - Sheila Kumari Singh
PY - 2026
DA - 2026/07/01
JO - Nature
DO - 10.1038/s41586-026-10641-1
UR - https://doi.org/10.1038/s41586-026-10641-1
AB - Glioblastoma is a lethal brain tumour for which current multimodal treatment rarely prevents recurrence 1 . Therapeutic failure is driven by extensive intratumoural cellular heterogeneity 2 with a microenvironment dominated by tumour-associated macrophages that sustain tumour growth and immunosuppression 3 . Although chimeric antigen receptor (CAR)-T cell therapies are being developed for glioblastoma, sustained response has been undermined by non-uniform antigen expression, antigen loss and microenvironmental barriers that are not directly engaged by tumour-targeting designs 4 . These limitations motivate new strategies that address the disease as a coupled tumour–immune system rather than a single malignant compartment. Here we use a multi-omic target discovery platform to identify GPNMB as a dual-compartment antigen in glioblastoma. Anti-GPNMB CAR-T cells showed potent anti-tumour activity, with long-term disease control in orthotopic patient-derived xenografts and syngeneic glioma models through concomitant depletion of GPNMB + tumour and immunosuppressive myeloid populations. By collapsing tumour control and microenvironmental reprogramming, these findings provide a new strategy for antigen selection and targeting in heterogenous, myeloid-rich solid cancers.
SN - 0028-0836
SN - 1476-4687
ER -