Fructose Metabolism Fuels Glioblastoma Growth, Offering New Immunotherapy Target

Northwestern Medicine scientists have made a groundbreaking discovery linking fructose metabolism within immune cells to the growth of glioblastoma, the most common and aggressive type of brain tumor. Published March 17 in the Proceedings of the National Academy of Sciences, the study identifies a novel pathway driving immune suppression in brain tumors and suggests that blocking fructose metabolism could enhance immunotherapy effectiveness and improve patient outcomes.

Glioblastoma: A Challenging Cancer

Glioblastoma is a particularly challenging cancer, with a five-year survival rate of less than 7% according to the National Brain Tumor Society [2]. Its resistance to treatment is largely attributed to the tumor microenvironment, a complex mix of cells surrounding the tumor.

The Role of Microglia and Fructose

The research focuses on microglia, immune cells that normally protect the brain and central nervous system, and immunosuppressive myeloid cells originating from the bone marrow. Microglia express a unique fructose transporter, GLUT5, allowing them to transport and metabolize fructose [1]. The study revealed that microglia uniquely express GLUT5 and are the only immune cells in the glioblastoma microenvironment capable of metabolizing fructose.

Surprisingly, the scientists found that fructose metabolism in microglia suppresses immune responses and promotes tumor growth. “We knew microglia use this fructose transporter as part of their normal biology, but we did not expect it to be this important for brain tumor growth,” said study senior author Jason Miska, assistant professor of neurological surgery at Northwestern University Feinberg School of Medicine [1].

Blocking Fructose Metabolism Enhances Immune Response

In mouse models, removing the fructose transporter (GLUT5) dramatically inhibited tumor growth [1]. This was accompanied by a strengthened immune response, including increased recognition of tumor cells, greater production of cytokines (signaling molecules that drive inflammation), and a rapid increase in CD8+ T-cells, the immune system’s primary cancer-killing cells.

“This not only makes the microglia themselves more inflammatory, but it also causes those T-cells and B-cells that are in the tumor to be more activated and create more inflammatory molecules that we have shown are required for rejection of brain tumors,” explained Leah Billingham, a Northwestern postdoctoral fellow and co-first author of the study [1].

Implications for Immunotherapy

These findings suggest that targeting microglial fructose metabolism could be a promising new therapeutic strategy for glioblastoma, potentially improving the response to immunotherapy. “The challenge with glioblastoma is that the standard of care has barely changed in 20 years,” Miska stated [1]. “That’s why identifying an entirely new therapeutic approach like this is so exciting.”

Fructose’s Unique Role in the Brain

Interestingly, Miska noted that fructose appears to have a different effect in the brain compared to other organs. While fructose consumption is often linked to inflammation in conditions like colon cancer and diabetic neuropathy, it seems to suppress inflammation in the brain, yet still aids tumor growth [1].

Future Research

The Northwestern team is now focused on identifying drugs that can block cells from absorbing fructose, with the goal of testing these inhibitors in preclinical trials, potentially in combination with existing brain tumor therapies or immunotherapies [1].

This research was supported by grants from the National Cancer Institute, Cancer Research Institute, National Institute of Neurological Disorders and Stroke, National Institute of General Medical Sciences, and others [1].