{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:57:20Z","timestamp":1792706240489,"version":"4.5.0"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"8129","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Glioblastoma is a lethal brain tumour for which current multimodal treatment rarely prevents recurrence\n                    <jats:sup>1<\/jats:sup>\n                    . Therapeutic failure is driven by extensive intratumoural cellular heterogeneity\n                    <jats:sup>2<\/jats:sup>\n                    with a microenvironment dominated by tumour-associated macrophages that sustain tumour growth and immunosuppression\n                    <jats:sup>3<\/jats:sup>\n                    . 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\n                    <jats:sup>4<\/jats:sup>\n                    . These limitations motivate new strategies that address the disease as a coupled tumour\u2013immune 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\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10641-1","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:49:09Z","timestamp":1782920949000},"page":"1013-1022","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Dual tumour\u2013myeloid targeting of glioblastoma with GPNMB CAR-T cells"],"prefix":"10.1038","volume":"656","author":[{"given":"Neil","family":"Savage","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Grewal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Vaseem","family":"Shaikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz J.","family":"Zemp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dillon","family":"Mckenna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Mikolajewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4432-9708","authenticated-orcid":false,"given":"Hinda","family":"Najem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Pyczek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuran","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6153-8782","authenticated-orcid":false,"given":"Mohamed A. B.","family":"Taleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas C.","family":"Asselstine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisha","family":"Anand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn C.","family":"Chafe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kui","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Maich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chirayu R.","family":"Chokshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardikkumar","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9805-8669","authenticated-orcid":false,"given":"Tiegan E.","family":"Korman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minomi","family":"Subapanditha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoya","family":"Tabunshchyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazanin","family":"Tatari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petar","family":"Miletic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2965-8506","authenticated-orcid":false,"given":"Abdelsimar T.","family":"Omar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bill","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9798-1551","authenticated-orcid":false,"given":"Jennifer A.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5514-2538","authenticated-orcid":false,"given":"Kevin R.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitra","family":"Venugopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-5540","authenticated-orcid":false,"given":"Thomas","family":"Kislinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9970-8695","authenticated-orcid":false,"given":"Amy B.","family":"Heimberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5663-8586","authenticated-orcid":false,"given":"Jason","family":"Moffat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0642-992X","authenticated-orcid":false,"given":"Douglas J.","family":"Mahoney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1272-5300","authenticated-orcid":false,"given":"Sheila K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"10641_CR1","doi-asserted-by":"publisher","first-page":"v1","DOI":"10.1093\/neuonc\/noac202","volume":"24","author":"QT Ostrom","year":"2022","unstructured":"Ostrom, Q. T. et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015\u20132019. Neuro-Oncology 24, v1\u2013v95 (2022).","journal-title":"Neuro-Oncology"},{"key":"10641_CR2","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1073\/pnas.1320611111","volume":"112","author":"M Meyer","year":"2015","unstructured":"Meyer, M. et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc. Natl Acad. Sci. USA 112, 851\u2013856 (2015).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10641_CR3","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/s41586-025-08633-8","volume":"640","author":"TE Miller","year":"2025","unstructured":"Miller, T. E. et al. Programs, origins and immunomodulatory functions of myeloid cells in glioma. Nature 640, 1072\u20131082 (2025).","journal-title":"Nature"},{"key":"10641_CR4","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.1016\/j.ymthe.2025.03.004","volume":"33","author":"SL Begley","year":"2025","unstructured":"Begley, S. L., O\u2019Rourke, D. M. & Binder, Z. A. CAR T cell therapy for glioblastoma: a review of the first decade of clinical trials. Mol. Ther. 33, 2454\u20132461 (2025).","journal-title":"Mol. Ther."},{"key":"10641_CR5","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJMoa043330","volume":"352","author":"R Stupp","year":"2005","unstructured":"Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987\u2013996 (2005).","journal-title":"N. Engl. J. Med."},{"key":"10641_CR6","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1101\/gad.261982.115","volume":"29","author":"JD Lathia","year":"2015","unstructured":"Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. L. & Rich, J. N. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203\u20131217 (2015).","journal-title":"Genes Dev."},{"key":"10641_CR7","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.trecan.2020.01.009","volume":"6","author":"BC Prager","year":"2020","unstructured":"Prager, B. C., Bhargava, S., Mahadev, V., Hubert, C. G. & Rich, J. N. Glioblastoma stem cells: driving resilience through chaos. Trends Cancer 6, 223\u2013235 (2020).","journal-title":"Trends Cancer"},{"key":"10641_CR8","doi-asserted-by":"publisher","first-page":"14720","DOI":"10.1073\/pnas.97.26.14720","volume":"97","author":"N Uchida","year":"2000","unstructured":"Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720\u201314725 (2000).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10641_CR9","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/nature03128","volume":"432","author":"KS Sheila","year":"2004","unstructured":"Sheila, K. S. et al. Identification of human brain tumour initiating cells. Nature 432, 396\u2013401 (2004).","journal-title":"Nature"},{"key":"10641_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-5-67","volume":"5","author":"G Liu","year":"2006","unstructured":"Liu, G. et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).","journal-title":"Mol. Cancer"},{"key":"10641_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.80","volume":"2","author":"JD Lathia","year":"2011","unstructured":"Lathia, J. D. et al. Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. Cell Death Dis. 2, e200 (2011).","journal-title":"Cell Death Dis."},{"key":"10641_CR12","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/ijc.2910600111","volume":"60","author":"MA Weterman","year":"1995","unstructured":"Weterman, M. A. et al. nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int. J. Cancer 60, 73\u201381 (1995).","journal-title":"Int. J. Cancer"},{"key":"10641_CR13","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1038\/s41588-025-02168-4","volume":"57","author":"A Spitzer","year":"2025","unstructured":"Spitzer, A. et al. Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics. Nat. Genet. 57, 1168\u20131178 (2025).","journal-title":"Nat. Genet."},{"key":"10641_CR14","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1007\/s00401-022-02506-4","volume":"144","author":"N Tatari","year":"2022","unstructured":"Tatari, N. et al. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers. Acta Neuropathol. 144, 1127\u20131142 (2022).","journal-title":"Acta Neuropathol."},{"key":"10641_CR15","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1016\/j.yexcr.2008.02.006","volume":"314","author":"SM Abdelmagid","year":"2008","unstructured":"Abdelmagid, S. M. et al. Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Exp. Cell. Res. 314, 2334\u20132351 (2008).","journal-title":"Exp. Cell. Res."},{"key":"10641_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-61931-1","volume":"10","author":"KB Biswas","year":"2020","unstructured":"Biswas, K. B. et al. GPNMB is expressed in human epidermal keratinocytes but disappears in the vitiligo lesional skin. Sci. Rep. 10, 4930 (2020).","journal-title":"Sci. Rep."},{"key":"10641_CR17","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-024-02831-w","volume":"148","author":"N Mikloajewicz","year":"2024","unstructured":"Mikloajewicz, N. et al. Functional profiling of murine glioma models highlights targetable immune evasion phenotypes. Acta Neuropathol. 148, 74 (2024).","journal-title":"Acta Neuropathol."},{"key":"10641_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28372-y","volume":"13","author":"N Abdelfattah","year":"2022","unstructured":"Abdelfattah, N. et al. Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target. Nat. Commun. 13, 767 (2022).","journal-title":"Nat. Commun."},{"key":"10641_CR19","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.cell.2018.06.021","volume":"174","author":"A Zeisel","year":"2018","unstructured":"Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999\u20131014.e1022 (2018).","journal-title":"Cell"},{"key":"10641_CR20","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","volume":"178","author":"C Neftel","year":"2019","unstructured":"Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178, 835\u2013849.e821 (2019).","journal-title":"Cell"},{"key":"10641_CR21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.ejca.2019.08.015","volume":"121","author":"LM Kopp","year":"2019","unstructured":"Kopp, L. M. et al. Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: a report from the Children\u2019s Oncology Group. Eur. J. Cancer 121, 177\u2013183 (2019).","journal-title":"Eur. J. Cancer"},{"key":"10641_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-021-00244-6","volume":"7","author":"LT Vahdat","year":"2021","unstructured":"Vahdat, L. T. et al. Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (\u201cMETRIC\u201d): a randomized multicenter study. NPJ Breast Cancer 7, 57 (2021).","journal-title":"NPJ Breast Cancer"},{"key":"10641_CR23","volume":"2","author":"SA Khan","year":"2021","unstructured":"Khan, S. A. et al. Efficacy and safety of glembatumumab vedotin in patients with advanced or metastatic squamous cell carcinoma of the lung (PrECOG 0504). JTO Clin. Res. Rep. 2, 100166 (2021).","journal-title":"JTO Clin. Res. Rep."},{"key":"10641_CR24","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1002\/cncr.31892","volume":"125","author":"PA Ott","year":"2019","unstructured":"Ott, P. A. et al. A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma. Cancer 125, 1113\u20131123 (2019).","journal-title":"Cancer"},{"key":"10641_CR25","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1177\/03009858231222216","volume":"61","author":"E Willis","year":"2024","unstructured":"Willis, E. et al. Humanization with CD34-positive hematopoietic stem cells in NOG-EXL mice results in improved long-term survival and less severe myeloid cell hyperactivation phenotype relative to NSG-SGM3 mice. Vet. Pathol. 61, 664\u2013674 (2024).","journal-title":"Vet. Pathol."},{"key":"10641_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2024.103079","volume":"5","author":"H Najem","year":"2024","unstructured":"Najem, H. et al. Protocol to quantify immune cell distribution from the vasculature to the glioma microenvironment on sequential immunofluorescence multiplex images. STAR Protoc. 5, 103079 (2024).","journal-title":"STAR Protoc."},{"key":"10641_CR27","doi-asserted-by":"publisher","first-page":"180","DOI":"10.4049\/jimmunol.154.1.180","volume":"154","author":"LD Shultz","year":"1995","unstructured":"Shultz, L. D. et al. Multiple defects in innate and adaptive immunologic function in NOD\/LtSz-scid mice. J. Immunol. 154, 180\u2013191 (1995).","journal-title":"J. Immunol."},{"key":"10641_CR28","doi-asserted-by":"publisher","first-page":"2558","DOI":"10.1016\/j.devcel.2025.04.027","volume":"60","author":"D Gu","year":"2025","unstructured":"Gu, D. et al. Stress-induced pro-inflammatory glioblastoma stem cells secrete TNFAIP6 to enhance tumor growth and induce suppressive macrophages. Dev. Cell 60, 2558\u20132575.e6 (2025).","journal-title":"Dev. Cell"},{"key":"10641_CR29","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1056\/NEJMoa2314390","volume":"390","author":"BD Choi","year":"2024","unstructured":"Choi, B. D. et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N. Engl. J. Med. 390, 1290\u20131298 (2024).","journal-title":"N. Engl. J. Med."},{"key":"10641_CR30","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1038\/s41591-024-02875-1","volume":"30","author":"CE Brown","year":"2024","unstructured":"Brown, C. E. et al. Locoregional delivery of IL-13R\u03b12-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat. Med. 30, 1001\u20131012 (2024).","journal-title":"Nat. Med."},{"key":"10641_CR31","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1038\/s41591-025-03745-0","volume":"31","author":"SJ Bagley","year":"2025","unstructured":"Bagley, S. J. et al. Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13R\u03b12 in recurrent glioblastoma: a phase 1 trial. Nat. Med. 31, 2778\u20132787 (2025).","journal-title":"Nat. Med."},{"key":"10641_CR32","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1093\/neuonc\/noae126","volume":"26","author":"AJ Hou","year":"2024","unstructured":"Hou, A. J. et al. IL-13R\u03b12\/TGF-\u03b2 bispecific CAR-T cells counter TGF-\u03b2-mediated immune suppression and potentiate anti-tumor responses in glioblastoma. Neuro Oncol. 26, 1850\u20131866 (2024).","journal-title":"Neuro Oncol."},{"key":"10641_CR33","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1016\/j.cell.2020.06.032","volume":"182","author":"Y Katzenelenbogen","year":"2020","unstructured":"Katzenelenbogen, Y. et al. Coupled scRNA-seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 182, 872\u2013885.e819 (2020).","journal-title":"Cell"},{"key":"10641_CR34","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s40478-024-01754-7","volume":"12","author":"F Yalcin","year":"2024","unstructured":"Yalcin, F. et al. Tumor associated microglia\/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma. Acta Neuropathol. Commun. 12, 50 (2024).","journal-title":"Acta Neuropathol. Commun."},{"key":"10641_CR35","doi-asserted-by":"publisher","first-page":"5336","DOI":"10.1016\/j.cell.2024.07.030","volume":"187","author":"DJ Kloosterman","year":"2024","unstructured":"Kloosterman, D. J. et al. Macrophage-mediated myelin recycling fuels brain cancer malignancy. Cell 187, 5336\u20135356.e5330 (2024).","journal-title":"Cell"},{"key":"10641_CR36","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.187684","author":"Y Liu","year":"2025","unstructured":"Liu, Y. Glycoprotein NMB mediates bidirectional GSC-TAM interactions to promote tumor progression. JCI Insight https:\/\/doi.org\/10.1172\/jci.insight.187684 (2025).","journal-title":"JCI Insight"},{"key":"10641_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-025-01553-2","volume":"17","author":"Y Du","year":"2025","unstructured":"Du, Y. et al. Spatial-reprogramming derived GPNMB+ macrophages interact with COL6A3+ fibroblasts to enhance vascular fibrosis in glioblastoma. Genome Med. 17, 136 (2025).","journal-title":"Genome Med."},{"key":"10641_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101232","volume":"297","author":"A Prabata","year":"2021","unstructured":"Prabata, A., Ikeda, K., Rahardini, E. P., Hirata, K. I. & Emoto, N. GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity. J. Biol. Chem. 297, 101232 (2021).","journal-title":"J. Biol. Chem."},{"key":"10641_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-99090-6","volume":"11","author":"B Nickl","year":"2021","unstructured":"Nickl, B., Qadri, F. & Bader, M. Anti-inflammatory role of Gpnmb in adipose tissue of mice. Sci. Rep. 11, 19614 (2021).","journal-title":"Sci. Rep."},{"key":"10641_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-20893-2","volume":"12","author":"A Rodriguez-Garcia","year":"2021","unstructured":"Rodriguez-Garcia, A. et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat. Commun. 12, 877 (2021).","journal-title":"Nat. Commun."},{"key":"10641_CR41","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.ccell.2025.11.009","volume":"44","author":"G Yagel","year":"2026","unstructured":"Yagel, G. et al. Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells. Cancer Cell 44, 519\u2013533.e10 (2026).","journal-title":"Cancer Cell"},{"key":"10641_CR42","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.ccell.2025.12.021","volume":"44","author":"J Mateus-Tique","year":"2026","unstructured":"Mateus-Tique, J. et al. Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth. Cancer Cell 44, 534\u2013550.e11 (2026).","journal-title":"Cancer Cell"},{"key":"10641_CR43","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.1016\/j.cell.2026.03.002","volume":"189","author":"Z Zhang","year":"2026","unstructured":"Zhang, Z. et al. A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy. Cell 189, 2898\u20132917.e42 (2026).","journal-title":"Cell"},{"key":"10641_CR44","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1111\/cas.14872","volume":"112","author":"CL Han","year":"2021","unstructured":"Han, C. L. et al. N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC. Cancer Sci. 112, 1911\u20131923 (2021).","journal-title":"Cancer Sci."},{"key":"10641_CR45","doi-asserted-by":"publisher","first-page":"4187","DOI":"10.1111\/cas.15090","volume":"112","author":"C Wang","year":"2021","unstructured":"Wang, C. et al. Glycoprotein non-metastatic melanoma protein B functions with growth factor signaling to induce tumorigenesis through its serine phosphorylation. Cancer Sci. 112, 4187\u20134197 (2021).","journal-title":"Cancer Sci."},{"key":"10641_CR46","doi-asserted-by":"publisher","first-page":"5294","DOI":"10.1038\/s41388-019-0793-7","volume":"38","author":"G Maric","year":"2019","unstructured":"Maric, G. et al. GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K\/AKT\/mTOR pathway signaling and \u03b2-catenin activity. Oncogene 38, 5294\u20135307 (2019).","journal-title":"Oncogene"},{"key":"10641_CR47","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.yexcr.2014.02.025","volume":"323","author":"C Fiorentini","year":"2014","unstructured":"Fiorentini, C. et al. GPNMB\/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity. Exp. Cell. Res. 323, 100\u2013111 (2014).","journal-title":"Exp. Cell. Res."},{"key":"10641_CR48","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3892\/ol.2021.13154","volume":"23","author":"JP Zhai","year":"2022","unstructured":"Zhai, J. P., Liu, Z. H., Wang, H. D., Huang, G. L. & Man, L. B. GPNMB overexpression is associated with extensive bone metastasis and poor prognosis in renal cell carcinoma. Oncol. Lett. 23, 36 (2022).","journal-title":"Oncol. Lett."},{"key":"10641_CR49","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.ccr.2013.08.001","volume":"24","author":"KPL Bhat","year":"2013","unstructured":"Bhat, K. P. L. et al. Mesenchymal differentiation mediated by NF-\u03baB promotes radiation resistance in glioblastoma. Cancer Cell 24, 331\u2013346 (2013).","journal-title":"Cancer Cell"},{"key":"10641_CR50","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/nature08712","volume":"463","author":"MS Carro","year":"2010","unstructured":"Carro, M. S. et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318\u2013325 (2010).","journal-title":"Nature"},{"key":"10641_CR51","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.ccell.2021.05.002","volume":"39","author":"T Hara","year":"2021","unstructured":"Hara, T. et al. Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma. Cancer Cell 39, 779\u2013792.e711 (2021).","journal-title":"Cancer Cell"},{"key":"10641_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104239","volume":"83","author":"A Xiong","year":"2022","unstructured":"Xiong, A., Zhang, J., Chen, Y., Zhang, Y. & Yang, F. Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM. eBioMedicine 83, 104239 (2022).","journal-title":"eBioMedicine"},{"key":"10641_CR53","volume":"1","author":"TJM van den Broek","year":"2025","unstructured":"van den Broek, T. J. M. et al. Single-cell spatial analysis of pediatric high-grade glioma reveals a novel population of SPP1+\/GPNMB+ myeloid cells with immunosuppressive and tumor-promoting capabilities. Neuro Oncol. 1, wuaf002 (2025).","journal-title":"Neuro Oncol."},{"key":"10641_CR54","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/s41586-023-05778-2","volume":"615","author":"AM Tousley","year":"2023","unstructured":"Tousley, A. M. et al. Co-opting signalling molecules enables logic-gated control of CAR T cells. Nature 615, 507\u2013516 (2023).","journal-title":"Nature"},{"key":"10641_CR55","doi-asserted-by":"publisher","DOI":"10.1126\/science.adl4237","volume":"386","author":"MS Simic","year":"2024","unstructured":"Simic, M. S. et al. Programming tissue-sensing T cells that deliver therapies to the brain. Science 386, eadl4237 (2024).","journal-title":"Science"},{"key":"10641_CR56","volume":"5","author":"A Schmidts","year":"2023","unstructured":"Schmidts, A. et al. Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13R\u03b12 are effective against heterogeneous glioblastoma. Neurooncol. Adv. 5, vdac185 (2023).","journal-title":"Neurooncol. Adv."},{"key":"10641_CR57","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1158\/2326-6066.CIR-16-0376","volume":"5","author":"G Krenciute","year":"2017","unstructured":"Krenciute, G. et al. Transgenic expression of IL15 improves antiglioma activity of IL13R\u03b12-CAR T cells but results in antigen loss variants. Cancer Immunol. Res. 5, 571\u2013581 (2017).","journal-title":"Cancer Immunol. Res."},{"key":"10641_CR58","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.1016\/j.celrep.2018.04.051","volume":"23","author":"MP Avanzi","year":"2018","unstructured":"Avanzi, M. P. et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep. 23, 2130\u20132141 (2018).","journal-title":"Cell Rep."},{"key":"10641_CR59","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/s41586-024-07443-8","volume":"630","author":"SA Yamada-Hunter","year":"2024","unstructured":"Yamada-Hunter, S. A. et al. Engineered CD47 protects T cells for enhanced antitumour immunity. Nature 630, 457\u2013465 (2024).","journal-title":"Nature"},{"key":"10641_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2020.100179","volume":"1","author":"CR Chokshi","year":"2020","unstructured":"Chokshi, C. R., Savage, N., Venugopal, C. & Singh, S. K. A patient-derived xenograft model of glioblastoma. STAR Protoc. 1, 100179 (2020).","journal-title":"STAR Protoc."},{"key":"10641_CR61","doi-asserted-by":"publisher","first-page":"101628","DOI":"10.1016\/j.xpro.2022.101628","volume":"3","author":"Y Suk","year":"2022","unstructured":"Suk, Y., Kieliszek, A., Mobilio, D., Venugopal, C. & Singh, S. K. Derivation and culturing of neural stem cells from human embryonic brain tissue. STAR Protoc. 3, 101628 (2022).","journal-title":"STAR Protoc."},{"key":"10641_CR62","doi-asserted-by":"publisher","first-page":"W98","DOI":"10.1093\/nar\/gkx247","volume":"45","author":"Z Tang","year":"2017","unstructured":"Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98\u2013W102 (2017).","journal-title":"Nucleic Acids Res."},{"key":"10641_CR63","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5","volume":"7","author":"P Bankhead","year":"2017","unstructured":"Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).","journal-title":"Sci. Rep."},{"key":"10641_CR64","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671\u2013675 (2012).","journal-title":"Nat. Methods"},{"key":"10641_CR65","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1534\/g3.117.041277","volume":"7","author":"T Hart","year":"2017","unstructured":"Hart, T. et al. Evaluation and design of genome-wide CRISPR\/SpCas9 knockout screens. G3 7, 2719\u20132727 (2017).","journal-title":"G3"},{"key":"10641_CR66","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/978-1-4939-3801-8_11","volume":"1458","author":"JA Hammill","year":"2016","unstructured":"Hammill, J. A., Afsahi, A., Bramson, J. L. & Helsen, C. W. Viral engineering of chimeric antigen receptor expression on murine and human T lymphocytes. Methods Mol. Biol. 1458, 137\u2013157 (2016).","journal-title":"Methods Mol. Biol."},{"key":"10641_CR67","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba7721","volume":"370","author":"J Cao","year":"2020","unstructured":"Cao, J. et al. A human cell atlas of fetal gene expression. Science 370, eaba7721 (2020).","journal-title":"Science"},{"key":"10641_CR68","doi-asserted-by":"publisher","unstructured":"Mikolajewicz, N. snRNA-seq, primary-recurrent GBM (Mikolajewicz cohort). figshare https:\/\/doi.org\/10.6084\/m9.figshare.25917628.v1 (2024).","DOI":"10.6084\/m9.figshare.25917628.v1"},{"key":"10641_CR69","doi-asserted-by":"publisher","unstructured":"Mikolajewicz, N. snRNA-seq, WT vs. Gpnmb-perturbed GL261 tumors (Savage et al. 2025). figshare https:\/\/doi.org\/10.6084\/m9.figshare.27643794.v1 (2024).","DOI":"10.6084\/m9.figshare.27643794.v1"},{"key":"10641_CR70","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1038\/s41593-021-00872-y","volume":"24","author":"KA Aldinger","year":"2021","unstructured":"Aldinger, K. A. et al. Spatial and cell type transcriptional landscape of human cerebellar development. Nat. Neurosci. 24, 1163\u20131175 (2021).","journal-title":"Nat. Neurosci."},{"key":"10641_CR71","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41586-021-03910-8","volume":"598","author":"A Bhaduri","year":"2021","unstructured":"Bhaduri, A. et al. An atlas of cortical arealization identifies dynamic molecular signatures. Nature 598, 200\u2013204 (2021).","journal-title":"Nature"},{"key":"10641_CR72","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.1016\/j.cell.2022.06.007","volume":"185","author":"J Biermann","year":"2022","unstructured":"Biermann, J. et al. Dissecting the treatment-naive ecosystem of human melanoma brain metastasis. Cell 185, 2591\u20132608.e2530 (2022).","journal-title":"Cell"},{"key":"10641_CR73","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.neuron.2021.10.036","volume":"110","author":"D Franjic","year":"2022","unstructured":"Franjic, D. et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110, 452\u2013469.e414 (2022).","journal-title":"Neuron"},{"key":"10641_CR74","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01097-9","volume":"14","author":"M Heming","year":"2022","unstructured":"Heming, M., Borsch, A. L., Wiendl, H. & Meyer Zu Horste, G. High-dimensional investigation of the cerebrospinal fluid to explore and monitor CNS immune responses. Genome Med. 14, 94 (2022).","journal-title":"Genome Med."},{"key":"10641_CR75","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/s41586-019-0903-2","volume":"566","author":"S Jakel","year":"2019","unstructured":"Jakel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543\u2013547 (2019).","journal-title":"Nature"},{"key":"10641_CR76","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/s41586-019-1654-9","volume":"574","author":"S Kanton","year":"2019","unstructured":"Kanton, S. et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature 574, 418\u2013422 (2019).","journal-title":"Nature"},{"key":"10641_CR77","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18231-z","volume":"11","author":"DW Kim","year":"2020","unstructured":"Kim, D. W. et al. The cellular and molecular landscape of hypothalamic patterning and differentiation from embryonic to late postnatal development. Nat. Commun. 11, 4360 (2020).","journal-title":"Nat. Commun."},{"key":"10641_CR78","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1101\/gr.256958.119","volume":"30","author":"E Khrameeva","year":"2020","unstructured":"Khrameeva, E. et al. Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains. Genome Res. 30, 776\u2013789 (2020).","journal-title":"Genome Res."},{"key":"10641_CR79","doi-asserted-by":"publisher","first-page":"25800","DOI":"10.1073\/pnas.2008762117","volume":"117","author":"SF Lau","year":"2020","unstructured":"Lau, S. F., Cao, H., Fu, A. K. Y. & Ip, N. Y. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer\u2019s disease. Proc. Natl Acad. Sci. USA 117, 25800\u201325809 (2020).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10641_CR80","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41586-019-1404-z","volume":"573","author":"L Schirmer","year":"2019","unstructured":"Schirmer, L. et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573, 75\u201382 (2019).","journal-title":"Nature"},{"key":"10641_CR81","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1093\/brain\/awab446","volume":"145","author":"S Smajic","year":"2022","unstructured":"Smajic, S. et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145, 964\u2013978 (2022).","journal-title":"Brain"},{"key":"10641_CR82","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1101","volume":"12","author":"HF Sun","year":"2022","unstructured":"Sun, H. F. et al. Single-cell RNA sequencing reveals cellular and molecular reprograming landscape of gliomas and lung cancer brain metastases. Clin. Transl. Med. 12, e1101 (2022).","journal-title":"Clin. Transl. Med."},{"key":"10641_CR83","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1038\/s43018-022-00475-x","volume":"3","author":"L Wang","year":"2022","unstructured":"Wang, L. et al. A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets. Nat. Cancer 3, 1534\u20131552 (2022).","journal-title":"Nat. Cancer"},{"key":"10641_CR84","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1038\/s41593-021-00940-3","volume":"24","author":"Y Yu","year":"2021","unstructured":"Yu, Y. et al. Interneuron origin and molecular diversity in the human fetal brain. Nat. Neurosci. 24, 1745\u20131756 (2021).","journal-title":"Nat. Neurosci."}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10641-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10641-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10641-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:03:18Z","timestamp":1787745798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10641-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":84,"journal-issue":{"issue":"8129","published-print":{"date-parts":[[2026,8,27]]}},"alternative-id":["10641"],"URL":"https:\/\/doi.org\/10.1038\/s41586-026-10641-1","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"assertion":[{"value":"9 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}