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<p>Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying distinct immune-cancer interactions are poorly understood. Here we identify γ-aminobutyric acid (GABA) as a female-specific driver of GBM-promoting immune response. We demonstrated that GABA receptor B (GABBR) signaling enhances the T cell suppressive function of granulocytic myeloid-derived suppressor cells (gMDSCs) from female mice by upregulating the cationic amino acid transporter 2–<span>L</span>-arginine–nitric oxide synthase 2 (NOS2) pathway. GABBR agonism promotes GBM growth in female preclinical models through gMDSCs, while GABBR antagonism extends survival and reduces NOS2 in tumor-infiltrating gMDSCs only in female mice. Immune cells from female participants with GBM have enriched GABA transcriptional signatures and a higher GABA concentration compared to male counterparts. Collectively, these results highlight the sex-specific immunomodulatory role of GABA in tumorigenesis, supporting future assessment of GABA pathway inhibitors for cancer immunotherapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Asmita Pathak,
  • Palavalasa Sravya,
  • Bruno Colon,
  • Erika Ciervo,
  • Yadi Zhou,
  • Oriana Y. Teran Pumar,
  • Brandon Emanuel León,
  • Jonathan Mitchell,
  • Pedro Henrique Assenza Tavares Coroa,
  • Beatriz Mateo-Victoriano,
  • Andrew J. Scott,
  • Durga Prasad Gannamedi,
  • Harrison K. A. Wong,
  • Li Zhang,
  • Juyeun Lee,
  • Kristen Kay,
  • Efe Karaca,
  • Diana H. Chin,
  • Haleh Amirian,
  • Irem Karaman,
  • Preyasha Shrestha,
  • Katelyn Sellick,
  • Danielle Dean,
  • Daniel Bilbao Cortes,
  • Jashodeep Datta,
  • Scott M. Welford,
  • Maria Clara Franco,
  • Kiran Kurmi,
  • Ashish H. Shah,
  • Feixiong Cheng,
  • Justin D. Lathia,
  • Priyamvada Rai,
  • David B. Lombard,
  • Costas A. Lyssiotis,
  • Dionysios C. Watson,
  • Michele Ceccarelli,
  • Daniel R. Wahl,
  • Defne Bayik

摘要

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying distinct immune-cancer interactions are poorly understood. Here we identify γ-aminobutyric acid (GABA) as a female-specific driver of GBM-promoting immune response. We demonstrated that GABA receptor B (GABBR) signaling enhances the T cell suppressive function of granulocytic myeloid-derived suppressor cells (gMDSCs) from female mice by upregulating the cationic amino acid transporter 2–L-arginine–nitric oxide synthase 2 (NOS2) pathway. GABBR agonism promotes GBM growth in female preclinical models through gMDSCs, while GABBR antagonism extends survival and reduces NOS2 in tumor-infiltrating gMDSCs only in female mice. Immune cells from female participants with GBM have enriched GABA transcriptional signatures and a higher GABA concentration compared to male counterparts. Collectively, these results highlight the sex-specific immunomodulatory role of GABA in tumorigenesis, supporting future assessment of GABA pathway inhibitors for cancer immunotherapy.