GRAND RAPIDS, Mich. (Sept. 8, 2025) — When it comes to their survival, cancer cells have a host of backup plans.
This is especially true of the nutrients that cancers use to grow and spread. In addition to relying on sugars like glucose to power their proliferation, some cancer cells also use ketones — metabolites produced from fats when the body is fasting or on a low carb diet — as an alternate fuel source.
Now, a new study by Van Andel Institute scientists suggest that the routes cancer cells use to process these different nutrients deeply influence cell behavior. They discovered an alternate, or non-canonical, path by which cancer cells convert a ketone called β-hydroxybutyrate (β-OHB) into acetyl-CoA, an essential metabolic building block for fatty acids and cholesterol that supports cell proliferation.
The findings, published today in the journal Nature Metabolism , could reshape how the relationship between diet and cancer is viewed.
"Cancer cells rely on a complex metabolic network to survive. Understanding the full scope of the nutrient sources that fuel cancer could help us find ways to interrupt this multi-layered defense," said Evan Lien, Ph.D. , an assistant professor in VAI's Department of Metabolism and Nutritional Programming and the study's corresponding author.
Lien and colleagues also found that cancer cells can leverage this alternative β-OHB pathway even when glucose, the body's main source of energy, is plentiful. This suggests that, depending on the circumstances, glucose may not always be the nutrient of choice for cells.
Today's findings add to an increasingly complex and nuanced understanding of how cells leverage a wide-ranging portfolio of nutrients to sustain themselves. For example, earlier research by VAI scientists suggests that cancer cells aren't the only ones to leverage ketones — immune cells do too. In 2023, VAI's Russell Jones, Ph.D. , found that T cells, the soldiers of the immune system, may prefer ketones over glucose as a fuel source . A later study by Jones's lab found that T cells tasked with fighting cancer also employ backup routes for producing acetyl-CoA. Jones is a co-author of today's study.
Many people are familiar with ketones through the lens of the ultra-low-carb keto diet. Although Lien's study shed important light on the metabolism of a specific ketone, it did not explore the effects of the keto diet or other similar dietary changes.
"There are no easy answers when it comes to diet, cancer and the immune system. That's why understanding how all the various pieces work together is incredibly important," Lien said. "Acetyl-CoA is essential to cell function, and our work shows that cancer cells can use different nutrients and different paths to produce it. These findings give us a fuller picture but there's still more to uncover."
Faith C. Kaluba and Thomas J. Rogers, Ph.D., are co-first authors of the study. Other authors include Yu-Jin Jeong, Ph.D., Rachel (Rae) J. House, Ph.D., Althea Waldhart, Kelly H. Sokol, Samuel R. Daniels, Cameron J. Lee, Joseph Longo, Ph.D., Amy Johnson, Vincent J. Sartori and Ryan D. Sheldon, Ph.D., of VAI.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award nos. R00CA255928 (Lien) and T32CA251066 (House; PI: Peter A. Jones); the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. R01AI165722 (Jones); Van Andel Institute's Metabolism and Nutrition (MeNu) Program (Lien); VAI MeNu Program Pathway to Independence Awards (Jeong and Longo); and a Canadian Institutes of Health Research Fellowship under award no. MFE-181903 (Longo). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.
