Dual tumour–myeloid targeting of glioblastoma with GPNMB CAR-T cells

作者：Neil Savage, Shan Grewal, Muhammad Vaseem Shaikh, Franz J. Zemp, Dillon McKenna, Nicholas Mikolajewicz, Hinda Najem, Joanna Pyczek, Jiuran Wei, Mo Taleb, Lucas Asselstine, Alisha Anand, Shawn C. Chafe, Kui Zhai, William T. Maich, Chirayu R. Chokshi, Hardikkumar Patel, Tiegan E. Korman, Minomi Subapanditha, Zoya Tabunshchyk, Nazanin Tatari, Petar Miletic, Di Chen, Sebastian Pacheco, Abdelsimar T. Omar, Bo Wang, 韩红, Jennifer A. Chan, Kevin R. Brown, Chitra Venugopal, Thomas Kislinger, Amy B. Heimberger, Jason Moffat, Douglas J. Mahoney, Sheila K. Singh · 发表于：Nature · 年份：2026 · DOI：10.1038/s41586-026-10641-1 · 被引用次数：5 · 研究领域：CAR-T cell therapy research、Glioma Diagnosis and Treatment、Single-cell and spatial transcriptomics

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.