Fructose Metabolism Fuels Glioblastoma Growth & Suppresses Immunity | Northwestern Medicine

A newly published study from Northwestern Medicine sheds light on a surprising mechanism driving the growth of glioblastoma, the most aggressive form of brain cancer. Researchers have discovered that specialized immune cells within the tumor, called microglia, uniquely metabolize fructose – a type of sugar – to suppress immune responses and fuel tumor progression. This finding, published in the Proceedings of the National Academy of Sciences, suggests a potential new therapeutic target for this devastating disease, which currently has a five-year survival rate of less than 7 percent.

Microglia and the Glioblastoma Microenvironment

Glioblastoma’s resistance to treatment is largely attributed to its complex tumor microenvironment. This environment includes immunosuppressive myeloid cells and, crucially, microglia – the resident immune cells of the brain and central nervous system. Microglia play a complex role in glioblastoma, contributing to both early tumor growth and maintaining unique metabolic and immunological processes within the tumor. What’s been less understood is *how* microglia contribute to the tumor’s ability to evade the body’s immune defenses.

Jason Miska, PhD, assistant professor of Neurological Surgery at Northwestern University and senior author of the study, explained the team’s initial curiosity. “There is more fructose in cerebral spinal fluid than there is in the plasma. The reasons for this are unknown, but what is known is that microglia express a lot of the transporter to metabolize it. So, we were curious about what this metabolism meant for brain tumors,” he said. Dr. Miska is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Learn more about his work.

The Role of GLUT5 and Fructose Metabolism

The research team’s investigation revealed that microglia express a unique fructose transporter, GLUT5, allowing them to efficiently transport and metabolize fructose. Using a combination of flow cytometry, bulk RNA-sequencing, and single-cell RNA-sequencing, they profiled microglia, macrophages, and glioma cell lines from mouse models of glioblastoma. This detailed analysis confirmed that microglia are the *only* immune cells within the glioblastoma microenvironment capable of metabolizing fructose.

Deleting GLUT5 in mouse models had a dramatic effect: it prevented tumor establishment entirely. This was accompanied by increased activation of both innate and adaptive immune responses. Specifically, researchers observed enhanced antigen presentation – the process by which immune cells recognize tumor cells – and a rapid expansion of cancer-killing CD8+ T-cells. Cytokine production, signaling molecules that coordinate immune responses, also increased.

Leah Billingham, PhD, a postdoctoral fellow in Dr. Miska’s laboratory and co-first author of the study, emphasized the interconnectedness of these immune responses. “This isn’t just solely the microglia doing something; this is an intricate interaction between the different parts of the immune system and how they are then impacting tumor rejection,” she explained. Meet the Miska Lab team.

Fructose in the Brain: A Unique Context

The findings are particularly intriguing given the broader understanding of fructose’s role in health. While high fructose consumption is often linked to inflammatory diseases like colon cancer and diabetic neuropathy, the Northwestern team found that in the brain, fructose appears to have the opposite effect – suppressing inflammation. Dr. Miska noted, “Fructose consumption is associated with so many bad inflammatory outcomes in patients. What’s interesting here is that in the brain, it seems to be working differently. It still helps the brain tumor grow, but now we’re seeing something very different in the brain than we see in the rest of the body.”

Implications for Immunotherapy and Future Research

These findings suggest that targeting microglial fructose metabolism could improve the effectiveness of immunotherapy for glioblastoma. Immunotherapy aims to harness the body’s own immune system to fight cancer, but glioblastoma’s immunosuppressive microenvironment often hinders these efforts. By blocking fructose metabolism in microglia, it may be possible to “release the brakes” on the immune system and allow it to more effectively attack the tumor.

The research team is now focused on identifying promising fructose transport inhibitors – compounds that can block the activity of GLUT5. These inhibitors will then be tested in preclinical trials, combined with standard-of-care therapies and immunotherapies, to assess their ability to sensitize glioblastoma cells to treatment. Read more about the study’s findings.

Next Steps: From Bench to Bedside

Dr. Miska’s team is actively pursuing the development of fructose transport inhibitors. The immediate focus is on identifying compounds that selectively target GLUT5 without causing significant side effects. Once promising candidates are identified, the next phase will involve rigorous preclinical testing in animal models. This will include evaluating the safety and efficacy of the inhibitors, both as standalone treatments and in combination with existing therapies for glioblastoma. Successful preclinical results would pave the way for clinical trials in human patients, a process that could take several years.