Abstract Glioblastoma (GBM) remains uniformly lethal, driven by profound intratumoral heterogeneity, and an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs). The identification of novel therapeutic targets is crucial for advancing promising therapies that address both tumor and TME. Here, we identify glycoprotein non-metastatic melanoma protein B (GPNMB) as a clinically relevant surface marker expressed on both GBM cells and TAMs. Genetic loss of GPNMB in GBM models reduced tumor cell proliferation, delayed intracranial tumor growth, and altered transcriptional programs linked to immune regulation and leukocyte activation, indicating GPNMB sustains both tumor fitness and an immunosuppressive niche. We generated both anti-human and anti-mouse GPNMB CAR-T cells showing potent activity: In orthotopic patient-derived xenografts, GPNMB CAR-T therapy induced complete tumor remission; murinized GPNMB CAR-Ts similarly produced sustained tumor control in syngeneic GBM models. In a humanized mouse model of recurrent GBM, anti-human GPNMB CAR-T therapy drove tumor regression in most animals despite a highly suppressive myeloid-rich TME. An integrated central nervous system myeloid single-cell RNA-sequencing atlas revealed GPNMB+ macrophages are enriched for lipid transport, and GPNMB expression correlates with immunosuppressive gene signatures. Consistent with this, GPNMB was preferentially expressed by immunosuppressive macrophages, and GPNMB CAR-Ts selectively eliminated immunosuppressive over pro-inflammatory macrophages in vitro and in vivo. Collectively, these data establish GPNMB CAR-T therapy as an extremely promising therapy inducing complete GBM remission in PDXs and immunocompetent models by simultaneously targeting GPNMB+ tumor cells and immunosuppressive macrophages. Citation Format: Sheila Kumari Singh, Neil Savage, Muhammad Vaseem Shaikh, Shan Grewal, Franz J. Zemp, Nick Mikolajewicz, Joanna Pyczek, Hinda Najem, Jeffrey Wei, Shawn C. Chafe, Kui Zhai, William Maich, CHIRAYU CHOKSHI, Nazanin Tatari, Dillon McKenna, Mohamed Taleb, Lucas Asselstine, Hong Han, Kevin Brown, Chitra Venugopal, Thomas Kislinger, Amy B. Heimberger, Jennifer A. Chan, Jason Moffat, Douglas J. Mahoney. GPNMB CAR-T cells target both glioblastoma and the tumor microenvironment to relieve immune suppression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4044.
Singh et al. (2026) studied this question.