The body utilizes various molecules as fuel sources, with glucose being the primary energy substrate for most cells. During fasting or carbohydrate restriction, the liver produces alternative molecules known as ketone bodies, including beta-hydroxybutyrate and acetoacetate. These ketones are normally used by the brain and muscle tissue when glucose is scarce, providing a metabolic backup system. The question of whether malignant cells can also utilize these ketone bodies for growth has become a major focus of modern cancer research. Understanding a tumor’s ability to switch fuel sources is central to developing metabolic strategies that aim to restrict a cancer cell’s supply chain.
Cancer Cell Reliance on Glucose
Most rapidly dividing cancer cells exhibit an altered metabolism characterized by a high rate of glucose uptake and conversion to lactate, even in the presence of sufficient oxygen. This phenomenon is known as the “Warburg Effect” or aerobic glycolysis. The preference for this seemingly inefficient pathway results in only a small amount of adenosine triphosphate (ATP) production per glucose molecule.
The primary advantage of this metabolic shift is not energy production, but the rapid generation of intermediate molecules diverted into biosynthetic pathways. These glycolytic intermediates serve as the carbon backbone for creating the building blocks required for proliferation, such as nucleotides, amino acids, and lipids. This dependence on glucose for both energy and construction materials makes glucose metabolism a defining metabolic characteristic of many malignancies.
The Biological Requirement for Ketone Use
To utilize ketone bodies for energy, a cell must possess a specific enzymatic pathway called ketolysis, which occurs inside the cell’s mitochondria. Ketolysis converts circulating ketone bodies back into acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle to generate ATP through oxidative phosphorylation. This process requires the presence and activity of several specialized enzymes.
Two specific enzymes are necessary for this conversion: D-beta-hydroxybutyrate dehydrogenase (BDH1) and Succinyl-CoA:3-ketoacid CoA transferase (SCOT), also known as OXCT1. BDH1 first converts beta-hydroxybutyrate into acetoacetate. SCOT then acts as the rate-limiting enzyme, converting acetoacetate into acetoacetyl-CoA, which is subsequently cleaved into two molecules of acetyl-CoA ready for the TCA cycle. Without sufficient expression of these ketolytic enzymes, a cell cannot use ketones as a fuel source.
Metabolic Flexibility and Ketone Utilization by Tumors
The ability of cancer cells to use ketones is not uniform across all tumor types, leading to the concept of metabolic heterogeneity. Some tumors are considered “metabolically inflexible” because they lack adequate levels of ketolytic enzymes like SCOT and BDH1, leaving them largely dependent on glucose. These glucose-dependent cells may be vulnerable to therapies that restrict glucose availability.
However, research has demonstrated that more aggressive and metabolically flexible tumor cells can upregulate these necessary enzymes, allowing them to thrive on ketones when glucose is scarce. Certain cancer types, including specific subtypes of glioblastoma, triple-negative breast cancer, and prostate cancer, show this upregulation of ketolytic machinery. This metabolic adaptation means that ketones, once thought to starve the tumor, can sometimes serve as an alternative, readily available fuel source for resistant cells.
In some tumor environments, a “two-compartment tumor metabolism” is observed, where non-cancerous cells within the tumor stroma produce ketones that are then consumed by the adjacent cancer cells. The cancer cells utilize these stromal-derived ketones for their own growth and mitochondrial oxidative metabolism. This highlights that for some tumor cells, ketones are not only usable but can actively drive tumor progression and metastasis, functioning as an “onco-metabolite.”
Research Implications for Metabolic Therapy
The knowledge that some tumors can adapt and utilize ketones has profoundly influenced the direction of current metabolic research. Simple dietary approaches aimed at restricting glucose may not be sufficient because they can inadvertently promote the use of ketones by flexible tumors. Therefore, therapeutic strategies are moving toward combination approaches that address both glucose reliance and the tumor’s potential for ketone utilization.
Researchers are now focused on developing targeted drugs that inhibit the ketolytic machinery, aiming to exploit the tumor’s reliance on these alternative fuels. Inhibiting the rate-limiting enzyme SCOT, for example, would block the conversion of ketones to acetyl-CoA, depriving the tumor cell mitochondria of a usable energy source. This targeted inhibition, often combined with glucose restriction, aims to create a metabolic blockade that starves the cancer cell by exploiting specific metabolic vulnerabilities.