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Peer-reviewedCC BY-NC-NDNature Cancer

GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells

  • Asmita Pathak1,2
  • Sravya Palavalasa3,4
  • Bruno Colon1
  • Erika Ciervo2
  • Yadi Zhou5
  • Oriana Teran Pumar1,2
  • Brandon Emanuel León1
  • Jonathan Mitchell1,6
  • Pedro Henrique Assenza Tavares Coroa7
  • Beatriz Mateo-Victoriano8
  • Andrew J. Scott3,4
  • Durga Prasad Gannamedi9
26 more authors
  • Harrison K. A. Wong10
  • Liping Zhang4
  • Juyeun Lee11
  • Kristen Kay11
  • Efe Karaca2
  • Diana H. Chin11
  • Haleh Amirian12
  • İrem Karaman7
  • Preyasha Shrestha1
  • Katelyn Sellick13
  • E. Danielle Dean13
  • Daniel Bilbao9,2
  • Jashodeep Datta12,2
  • Scott M. Welford8,2
  • María Clara Franco14,15
  • Kiran Kurmi1,2
  • Ashish Harish Shah16,2
  • Feixiong Cheng17,5
  • Justin Durla Lathia17,11,18
  • Priyamvada Rai8,2
  • David B. Lombard9,19,2
  • Costas Andreas Lyssiotis10,4
  • Dionysios C. Watson7,2
  • Michele Ceccarelli2
  • Daniel Richard Wahl20,3,4
  • Defne Bayık21,22
22 affiliations
  1. 1Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  2. 2Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
  3. 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
  4. 4Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
  5. 5Genomic Medicine Institute, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA
  6. 6Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  7. 7Medical Oncology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  8. 8Department of Radiation Oncology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  9. 9Department of Pathology and Laboratory Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  10. 10Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
  11. 11Department of Cancer Sciences, Cleveland Clinic Research, Cleveland, OH, USA
  12. 12Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  13. 13Vanderbilt University Medical Center, Nashville, TN, USA
  14. 14Center for Translational Science, Florida International University, Port St. Lucie, FL, USA
  15. 15Department of Cellular and Molecular Medicine, Florida International University, Miami, FL, USA
  16. 16Department of Neurosurgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
  17. 17Case Comprehensive Cancer Center, Cleveland, OH, USA
  18. 18Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
  19. 19Miami VA Healthcare System, Miami, FL, USA
  20. 20Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA
  21. 21Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA. [email protected]
  22. 22Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. [email protected]
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Abstract

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

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Cite

BibTeXRIS
BibTeX
@article{pathak2026gaba,
  title = {{GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells}},
  author = {Asmita Pathak and Sravya Palavalasa and Bruno Colon and Erika Ciervo and Yadi Zhou and Oriana Teran Pumar and Brandon Emanuel León and Jonathan Mitchell and Pedro Henrique Assenza Tavares Coroa and Beatriz Mateo-Victoriano and Andrew J. Scott and Durga Prasad Gannamedi and Harrison K. A. Wong and Liping Zhang and Juyeun Lee and Kristen Kay and Efe Karaca and Diana H. Chin and Haleh Amirian and İrem Karaman and Preyasha Shrestha and Katelyn Sellick and E. Danielle Dean and Daniel Bilbao and Jashodeep Datta and Scott M. Welford and María Clara Franco and Kiran Kurmi and Ashish Harish Shah and Feixiong Cheng and Justin Durla Lathia and Priyamvada Rai and David B. Lombard and Costas Andreas Lyssiotis and Dionysios C. Watson and Michele Ceccarelli and Daniel Richard Wahl and Defne Bayık},
  journal = {Nature Cancer},
  year = {2026},
  month = jun,
  doi = {10.1038/s43018-026-01192-5},
  url = {https://doi.org/10.1038/s43018-026-01192-5},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells
AU  - Asmita Pathak
AU  - Sravya Palavalasa
AU  - Bruno Colon
AU  - Erika Ciervo
AU  - Yadi Zhou
AU  - Oriana Teran Pumar
AU  - Brandon Emanuel León
AU  - Jonathan Mitchell
AU  - Pedro Henrique Assenza Tavares Coroa
AU  - Beatriz Mateo-Victoriano
AU  - Andrew J. Scott
AU  - Durga Prasad Gannamedi
AU  - Harrison K. A. Wong
AU  - Liping Zhang
AU  - Juyeun Lee
AU  - Kristen Kay
AU  - Efe Karaca
AU  - Diana H. Chin
AU  - Haleh Amirian
AU  - İrem Karaman
AU  - Preyasha Shrestha
AU  - Katelyn Sellick
AU  - E. Danielle Dean
AU  - Daniel Bilbao
AU  - Jashodeep Datta
AU  - Scott M. Welford
AU  - María Clara Franco
AU  - Kiran Kurmi
AU  - Ashish Harish Shah
AU  - Feixiong Cheng
AU  - Justin Durla Lathia
AU  - Priyamvada Rai
AU  - David B. Lombard
AU  - Costas Andreas Lyssiotis
AU  - Dionysios C. Watson
AU  - Michele Ceccarelli
AU  - Daniel Richard Wahl
AU  - Defne Bayık
PY  - 2026
DA  - 2026/06/23
JO  - Nature Cancer
DO  - 10.1038/s43018-026-01192-5
UR  - https://doi.org/10.1038/s43018-026-01192-5
AB  - Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.
SN  - 2662-1347
ER  -