{ "abstract": "MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. Here, we show that MALT1 plays a key role in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis within macrophages, leading to macrophage migration and polarization toward an immunosuppressive phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage “M1-like” phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in increased immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. Further, the addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, which may enhance the efficacy of this standard-of-care chemotherapeutic. Together, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM. Graphical abstract. The effects of tumor cell-induced CARD9-BCL10-MALT1 (CBM) activation (left) and MALT1 protease inhibition (right) on GBM associated macrophages in the tumor microenvironment. Cartoon of cellular components of a GBM tumor with an immunosuppressive TME characterized by “M2-like macrophages” (left) and conversion to a more immune-reactive tumor microenvironment characterized by “M1-like macrophages and increased effector T-cells (right) as a result of MALT1 protease inhibition.", "abstract_shown": true, "affiliations": [ "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, US. julianahazambuja@gmail.com", "Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, US. julianahazambuja@gmail.com", "UPMC Hillman Cancer Center, Pittsburgh, PA, US. julianahazambuja@gmail.com", "Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, US", "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, US", "Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, US", "Medical Scientist Training Program (MSTP), University of Pittsburgh School of Medicine, Pittsburgh, PA, US", "Biosciences Graduate Degree Program, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil", "Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, US", "Biomedical Sciences Program, College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, US", "Rangos Research Center Animal Imaging Core, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, US", "UPMC Hillman Cancer Center, Pittsburgh, PA, US", "BlueSphere Bio, Pittsburgh, PA, US", "Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, US", "Nimble Therapeutics, Madison, WI, US", "Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, King of Prussia, PA, US", "Sanofi, Cambridge, MA, US", "Division of Hematology and Oncology, Cornell University, New York, NY, US", "Josep Carreras Leukaemia Research Institute, Barcelona, Spain", "Department of Medicine, University of Pittsburgh, Pittsburgh, PA, US", "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, US. Lucas.Peter@mayo.edu", "Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, US. Lucas.Peter@mayo.edu", "Mayo Clinic Comprehensive Cancer Center, Rochester, MN, US. Lucas.Peter@mayo.edu", "UPMC Hillman Cancer Center, Pittsburgh, PA, US. Lucas.Peter@mayo.edu", "Department of Pediatrics, Mayo Clinic, Rochester, MN, US. McAllister.Linda@mayo.edu", "Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, US. McAllister.Linda@mayo.edu", "Mayo Clinic Comprehensive Cancer Center, Rochester, MN, US. McAllister.Linda@mayo.edu", "UPMC Hillman Cancer Center, Pittsburgh, PA, US. McAllister.Linda@mayo.edu" ], "article_type": null, "arxiv": null, "author_total": 24, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Juliana H. Azambuja", "orcid": "0000-0002-2416-7724" }, { "affs": [ 3, 4 ], "name": "Saigopalakrishna S. Yerneni", "orcid": "0000-0003-4837-5592" }, { "affs": [ 5 ], "name": "Lisa M. Maurer", "orcid": "0000-0003-0492-9805" }, { "affs": [ 5, 6 ], "name": "Hannah E. Crentsil", "orcid": "0000-0002-2076-0950" }, { "affs": [ 7, 8 ], "name": "Gabriela Nogueira Debom", "orcid": "0000-0002-3921-479X" }, { "affs": [ 5 ], "name": "Linda R. Klei", "orcid": "0000-0001-7056-183X" }, { "affs": [ 9, 5 ], "name": "Mei Smyers", "orcid": "0009-0007-6935-2855" }, { "affs": [ 8 ], "name": "Chaim T. Sneiderman", "orcid": "0009-0007-3726-6143" }, { "affs": [ 10 ], "name": "Kristina Elsa Schwab" }, { "affs": [ 11 ], "name": "Rajesh Acharya", "orcid": "0000-0002-3698-1977" }, { "affs": [ 4 ], "name": "Aivi T. Nguyen", "orcid": "0000-0003-1809-9451" }, { "affs": [ 4 ], "name": "Josie L. Emery" }, { "affs": [ 5, 6 ], "name": "John W. Little", "orcid": "0000-0003-2034-2684" }, { "affs": [ 4 ], "name": "Jeffrey A. Meridew" }, { "affs": [ 10 ], "name": "Yijen Lin Wu", "orcid": "0000-0001-9509-5417" }, { "affs": [ 12, 5 ], "name": "Prasanna Ekambaram", "orcid": "0000-0001-9568-617X" }, { "affs": [ 4, 13 ], "name": "Dong Hu", "orcid": "0009-0009-3537-8605" }, { "affs": [ 14, 15 ], "name": "Pete J. Gough" }, { "affs": [ 15, 16 ], "name": "John Bertin", "orcid": "0000-0001-9048-1650" }, { "affs": [ 17, 18 ], "name": "Ari M. Melnick", "orcid": "0000-0002-8074-2287" }, { "affs": [ 8 ], "name": "Gary Kohanbash", "orcid": "0000-0002-3953-8022" }, { "affs": [ 19, 11 ], "name": "Riyue Bao", "orcid": "0000-0002-6105-1704" }, { "affs": [ 20, 21, 22, 23 ], "name": "Peter C. Lucas", "orcid": "0000-0003-4880-7172" }, { "affs": [ 24, 25, 26, 27 ], "name": "Linda M. McAllister‐Lucas", "orcid": "0000-0002-9875-5043" } ], "bibtex": "https://research.draconitic.com/paper/3ydybz05ftntw.bib", "cited_by": 5, "doi": "10.1038/s41467-026-76572-7", "fulltext_url": null, "id": "3ydybz05ftntw", "issns": [ "2041-1723" ], "landing_url": "https://doi.org/10.1038/s41467-026-76572-7", "language": "en", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2403|Immune cells in cancer" ] ], "openalex": "W7202079176", "pdf_url": null, "pmcid": "PMC11463364", "pmid": "39386586", "published": "2026-08-10", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/3ydybz05ftntw.ris", "sources": [ { "first_seen": "2026-11-05T13:20:55Z", "native_id": "W7202079176", "source": "openalex", "url": "https://doi.org/10.1038/s41467-026-76572-7" } ], "subjects": [ { "field": "biology", "origin": "openalex:2403|Immune cells in cancer", "subfield": "immunology" } ], "title": "MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice", "title_text": "MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice", "type": "peer-reviewed", "updated_at": "2026-11-08T13:20:46Z", "url": "https://research.draconitic.com/paper/3ydybz05ftntw", "venue": "Nature Communications", "versions": [] }