Summary: Glioblastoma, the most common and lethal form of brain cancer, exhibits striking differences between men and women in its incidence, treatment responses, and survival rates. A groundbreaking study has identified a critical, sex-specific biological mechanism that explains how glioblastoma exploits different immune pathways depending on the biological sex of the subject.
A new study revealed that the neurotransmitter GABA (gamma-aminobutyric acid) selectively fuels tumor growth in females. GABA reprograms the cellular metabolism of granulocytic myeloid-derived suppressor cells (MDSCs), a class of immune cells that suppress anti-tumor T-cell activity, making them highly immunosuppressive specifically in females.
In contrast, male models utilize monocytic MDSCs driven by entirely separate mechanisms. By blocking GABA receptors, the team successfully dismantled this protective shield and improved survival outcomes exclusively in female laboratory models, a breakthrough that opens the door to sex-specific immunotherapies for brain cancer.
Key Facts
- The Cellular Split: Men with glioblastoma exhibit higher levels of monocytic MDSCs, whereas granulocytic MDSCs correlate with worse clinical outcomes exclusively for women.
- GABA’s Metabolic Takeover: The neurotransmitter GABA directly alters cellular metabolism and boosts the immunosuppressive capabilities of granulocytic MDSCs only in females.
- Targeted Therapeutic Success: Pharmacologically blocking GABA receptors dismantled the tumor-protecting immune shield and improved outcomes in female models, while exerting zero effect on males.
- Human Tissue Validation: Biopsies from human female glioblastoma patients confirmed significantly higher levels of both GABA and GABA receptors inside granulocytic MDSCs compared to male tissue samples.
- Broad Oncology Implications: Because suppressive MDSCs are heavily recruited by many other aggressive cancer types, these sex-specific metabolic findings may have therapeutic applications far beyond glioblastoma.
Source: University of Miami
Researchers have identified a critical biological difference in how glioblastoma develops in male and female laboratory models, pinpointing an immune pathway that fuels tumor growth only in females.
The study shows that the neurotransmitter GABA boosts the cancer-protecting activity of immune cells in female models—but not male ones—and blocking that signal improved outcomes. The findings could one day lead to new drug targets and therapeutics specifically for women.
Men and women experience many diseases very differently. Certain diseases present more commonly in one sex than in another, some conditions may cause different symptoms in men and women, and some treatments work better or not at all for one sex over the other.
Cancer is no exception. There are major differences in male and female immune systems, and this system is critical both for cancer’s growth and for successfully becoming cancer-free. For example, some immunotherapies work better in men than in women and vice versa.
Glioblastoma, the most common and fatal form of brain cancer, is more common and more deadly in men than in women. The reasons behind this difference — and how the cancer’s biology differs between men and women — remain largely unclear.
Led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami’s Miller School of Medicine, the study has identified a cellular mechanism that differs between male and female laboratory models with glioblastoma.
It was published in the journal Nature Cancer and led by Defne Bayik, Ph.D., an assistant professor of molecular and cellular pharmacology, and Asmita Pathak, Ph.D., a former postdoctoral fellow of the Bayik Lab.
“We have a growing appreciation that cancer doesn’t act the same way in men and women. There are differences in incidence rates; there are differences in treatment responses; there are differences in outcomes,” Bayik said. “But we don’t really have a good fundamental understanding of the mechanisms underlying these observational studies.”
To uncover that mechanism for glioblastoma, Bayik and her colleagues focused on a certain class of immune cells in the brain known as myeloid-derived suppressor cells, or MDSCs. As their name suggests, these cells suppress other cells’ immune activity, especially that of T cells. In healthy contexts, their activity is important for regulating the immune system and keeping inflammation under control.
But in the context of cancer, these cells are often recruited by tumors to suppress surrounding T cells and other immune cells, protecting cancerous cells from the rest of the immune system and allowing them to grow unchecked.
In previous work, Bayik found sex-specific differences in the immune landscape of glioblastoma, with higher levels of monocytic myeloid-derived suppressor cells (MDSCs) associated with disease in male laboratory models, while granulocytic MDSCs play a more prominent role in females. In studies of human glioblastoma tumors, she observed a similar pattern: Men tend to have more monocytic MDSCs within their tumors, whereas granulocytic MDSCs—or proteins associated with these cells—correlate with worse outcomes for women but not for men.
In the new study, Bayik and her colleagues wanted to understand what drives this difference. How do granulocytic MDSCs act to promote cancer growth in female but not male laboratory models? In a previous study, she’d found several drug candidates that are predicted to act on granulocytic MDSCs. A few of these candidate drugs target proteins related to GABA, a brain signaling molecule also known as a neurotransmitter.
By exposing different populations of MDSCs to GABA in the lab, the scientists found that the neurotransmitter specifically affects cellular metabolism only in female granulocytic MDSCs. The process is unaffected in male MDSCs. They also found that this reprogramming of the cells’ metabolism by GABA made the granulocytic MDSCs more immunosuppressive. Finally, they found that blocking the GABA receptor in female laboratory models with glioblastoma improved their outcome, but this had no effect on male laboratory models with the cancer.
The researchers found that many of their lab findings held up in human samples donated by patients with glioblastoma. Tumor biopsies from women had higher levels of GABA and the GABA receptor in granulocytic MDSCs than did those from men. They also found that GABA reprograms granulocytic MDSC metabolism in women as it does in lab models.
These findings point to the potential for a sex-specific treatment for glioblastoma, Bayik said. She’s currently working to understand the basis for the difference in cellular metabolism in these immune cells between male and female laboratory models.
Further uncovering the mechanism of this sex difference will help her and other scientists find new potential drug targets for the disease. And MDSCs are involved in many other types of cancer, so drugs that target these cells could have broader applications than just glioblastoma.
“Glioblastoma may be more common in men, but women still constitute 40% of patients,” said Bayik. “By identifying these differences, we can better tailor treatments for both men and women.”
Key Questions Answered:
A: In a healthy individual, myeloid-derived suppressor cells (MDSCs) act as essential brakes for the immune system, shutting down active T cells to keep systemic inflammation and autoimmune damage under control. However, glioblastoma tumors essentially hijack this mechanism. The tumor recruits these immature immune cells into the surrounding brain space and forces them to work as an immunosuppressive shield. This shield paralyzes local T cells, hiding the cancerous cells from the immune system and allowing the tumor to grow completely unchecked.
A: The study uncovered a distinct cellular divergence in how male and female immune cells are wired. In females, granulocytic MDSCs express significantly higher numbers of GABA receptors and are uniquely sensitive to the neurotransmitter. When GABA binds to these female receptors, it triggers a cascade that completely reprograms the cell’s internal metabolism, shifting it into a hyper-active, immunosuppressive state. In males, the primary immune cells involved are monocytic MDSCs, which do not experience this metabolic shift when exposed to GABA, leaving their behavior completely unaltered by the neurotransmitter.
A: Historically, clinical trials and drug developments have treated glioblastoma as a uniform disease, resulting in immunotherapies that fail unpredictably or work better in one sex than the other. This research proves that male and female glioblastomas utilize entirely different cellular workforces to blind the immune system. A drug designed to block GABA receptors could be a life-saving, highly targeted treatment for women, yet it would be a total failure if prescribed to men. Identifying these exact biological mechanisms allows scientists to design tailored, sex-specific treatment protocols that maximize efficacy for both patient populations.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain cancer research news
Author: Sandy Van
Source: Sylvester Comprehensive Cancer Center
Contact: Sandy Van – Sylvester Comprehensive Cancer Center
Image: The image is credited to Neuroscience News
Original Research: Open access.
“GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells” by 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. Nature Cancer
DOI:10.1038/s43018-026-01192-5
Abstract
GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells
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.
