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Peer-reviewedCC BY-NC-NDNature Communications

MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice

  • Juliana H. Azambuja1,2,3
  • Saigopalakrishna S. Yerneni4,5
  • Lisa M. Maurer6
  • Hannah E. Crentsil6,7
  • Gabriela Nogueira Debom8,9
  • Linda R. Klei6
  • Mei Smyers10,6
  • Chaim T. Sneiderman9
  • Kristina Elsa Schwab11
  • Rajesh Acharya12
  • Aivi T. Nguyen5
  • Josie L. Emery5
12 more authors
  • John W. Little6,7
  • Jeffrey A. Meridew5
  • Yijen Lin Wu11
  • Prasanna Ekambaram13,6
  • Dong Hu5,14
  • Pete J. Gough15,16
  • John Bertin16,17
  • Ari M. Melnick18,19
  • Gary Kohanbash9
  • Riyue Bao20,12
  • Peter C. Lucas21,22,23,24
  • Linda M. McAllister‐Lucas25,26,27,28
28 affiliations
  1. 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, US. [email protected]
  2. 2Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, US. [email protected]
  3. 3UPMC Hillman Cancer Center, Pittsburgh, PA, US. [email protected]
  4. 4Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, US
  5. 5Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, US
  6. 6Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, US
  7. 7Medical Scientist Training Program (MSTP), University of Pittsburgh School of Medicine, Pittsburgh, PA, US
  8. 8Biosciences Graduate Degree Program, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
  9. 9Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, US
  10. 10Biomedical Sciences Program, College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, US
  11. 11Rangos Research Center Animal Imaging Core, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, US
  12. 12UPMC Hillman Cancer Center, Pittsburgh, PA, US
  13. 13BlueSphere Bio, Pittsburgh, PA, US
  14. 14Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, US
  15. 15Nimble Therapeutics, Madison, WI, US
  16. 16Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, King of Prussia, PA, US
  17. 17Sanofi, Cambridge, MA, US
  18. 18Division of Hematology and Oncology, Cornell University, New York, NY, US
  19. 19Josep Carreras Leukaemia Research Institute, Barcelona, Spain
  20. 20Department of Medicine, University of Pittsburgh, Pittsburgh, PA, US
  21. 21Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, US. [email protected]
  22. 22Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, US. [email protected]
  23. 23Mayo Clinic Comprehensive Cancer Center, Rochester, MN, US. [email protected]
  24. 24UPMC Hillman Cancer Center, Pittsburgh, PA, US. [email protected]
  25. 25Department of Pediatrics, Mayo Clinic, Rochester, MN, US. [email protected]
  26. 26Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, US. [email protected]
  27. 27Mayo Clinic Comprehensive Cancer Center, Rochester, MN, US. [email protected]
  28. 28UPMC Hillman Cancer Center, Pittsburgh, PA, US. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{azambuja2026malt1,
  title = {{MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice}},
  author = {Juliana H. Azambuja and Saigopalakrishna S. Yerneni and Lisa M. Maurer and Hannah E. Crentsil and Gabriela Nogueira Debom and Linda R. Klei and Mei Smyers and Chaim T. Sneiderman and Kristina Elsa Schwab and Rajesh Acharya and Aivi T. Nguyen and Josie L. Emery and John W. Little and Jeffrey A. Meridew and Yijen Lin Wu and Prasanna Ekambaram and Dong Hu and Pete J. Gough and John Bertin and Ari M. Melnick and Gary Kohanbash and Riyue Bao and Peter C. Lucas and Linda M. McAllister‐Lucas},
  journal = {Nature Communications},
  year = {2026},
  month = aug,
  doi = {10.1038/s41467-026-76572-7},
  url = {https://doi.org/10.1038/s41467-026-76572-7},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice
AU  - Juliana H. Azambuja
AU  - Saigopalakrishna S. Yerneni
AU  - Lisa M. Maurer
AU  - Hannah E. Crentsil
AU  - Gabriela Nogueira Debom
AU  - Linda R. Klei
AU  - Mei Smyers
AU  - Chaim T. Sneiderman
AU  - Kristina Elsa Schwab
AU  - Rajesh Acharya
AU  - Aivi T. Nguyen
AU  - Josie L. Emery
AU  - John W. Little
AU  - Jeffrey A. Meridew
AU  - Yijen Lin Wu
AU  - Prasanna Ekambaram
AU  - Dong Hu
AU  - Pete J. Gough
AU  - John Bertin
AU  - Ari M. Melnick
AU  - Gary Kohanbash
AU  - Riyue Bao
AU  - Peter C. Lucas
AU  - Linda M. McAllister‐Lucas
PY  - 2026
DA  - 2026/08/10
JO  - Nature Communications
DO  - 10.1038/s41467-026-76572-7
UR  - https://doi.org/10.1038/s41467-026-76572-7
AB  - 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.
SN  - 2041-1723
ER  -