Ketone Body β-Hydroxybutyrate Enhances CAR T Cell Therapy Efficacy in Preclinical Studies, Human Trials Underway
核心洞察
Researchers at Arc Institute (搜索) and Stanford University discovered that β-hydroxybutyrate (搜索) (BHB (搜索)), a naturally occurring ketone body, significantly enhances CAR T cell metabolic fitness and antitumor activity across multiple cancer models including lymphoma (搜索), leukemia (搜索), and pancreatic cancer (搜索).
The study demonstrated that BHB (搜索) supplementation improved CAR T cell expansion and tumor killing by fueling mitochondrial respiration through the TCA cycle (搜索), while also reprogramming gene expression to favor activation over exhaustion markers.
A clinical trial testing BHB (搜索) supplementation in Large B-cell Lymphoma (搜索) patients is already underway, offering a potentially safe and cost-effective approach to enhance immunotherapy without genetic modification.
A naturally occurring byproduct of liver metabolism—the ketone body β-hydroxybutyrate (搜索) (BHB (搜索))—can strengthen the fitness and antitumor activity of CAR T cells (搜索), according to groundbreaking research published March 6, 2026 in the journal Cell. The findings from Arc Institute (搜索) and Stanford University scientists, together with colleagues from the University of Pennsylvania, highlight a potential new way to enhance cancer immunotherapies through metabolic intervention.
Ketogenic Diet Shows Promise in Preclinical Models
The research team, led by Maayan Levy, Assistant Professor of Pathology at Stanford and Arc Innovation Investigator in Residence, began by investigating whether dietary factors could influence CAR T efficacy. Testing six different diets in mice—including high-fiber, high-protein, Western, and ketogenic diets—researchers found that only the ketogenic diet showed consistently improved tumor control following CAR T therapy.
"CAR T cell therapy has revolutionized treatment for certain blood cancers (搜索), yet many patients still fail to respond or eventually relapse," says Levy. "This challenge has led scientists to search for new, practical ways to strengthen T cell metabolism, without presenting additional burdens on patients."
To understand this effect, the researchers examined metabolic differences and found that ketogenic-fed mice had higher levels of BHB (搜索) relative to all other groups, pointing to BHB as the defining metabolic difference among the keto-fed mice.
BHB Supplementation Replicates Dietary Benefits
Recognizing that ketogenic diets can be difficult for cancer patients to sustain due to their strict macronutrient requirements, potential risk of nutrient deficiencies, and cancer-related appetite loss, the team explored whether BHB (搜索) supplementation alone could provide the same benefit. Across several cancer models, including lymphoma (搜索), leukemia (搜索), and even a notoriously resistant pancreatic cancer (搜索) model, BHB supplementation improved CAR T cell expansion and tumor killing, closely mirroring the observed effects of the full diet.
"Importantly, these improvements were seen only in the presence of CAR T cells (搜索)—BHB (搜索) alone had little or no impact in mice treated with non-engineered T cells," says Levy. "This shows that BHB improves CAR T efficacy by enhancing immune function rather than acting directly on tumors."
Metabolic Mechanisms Revealed
Using stable isotope tracing, the team tracked how CAR T cells (搜索) used BHB (搜索) as fuel and found that the cells rapidly incorporated it into the TCA cycle (搜索), the central pathway that powers mitochondria, helping the cells create more usable energy and withstand the stress of fighting cancer. Further tests confirmed that BHB-exposed CAR T cells consumed more oxygen and produced more ATP, a key energy molecule, than standard CAR T cells.
Single-cell RNA sequencing revealed that BHB (搜索)-treated CAR T cells (搜索) expressed more genes associated with activation and tumor killing, and fewer associated with exhaustion—changes that support stronger and longer-lasting immune responses. ATAC-seq and CUT&RUN analysis showed that BHB makes key regions easier for CAR T cells to access, controlling genes that help the cells make energy, stay healthy, and fight cancer more effectively.
Direct Metabolic Requirement Confirmed
To test whether T cells need to metabolize BHB (搜索) for it to aid CAR T cell therapy, the researchers used CRISPR to knock out BDH1 (搜索), the enzyme that converts BHB into usable energy. Without BDH1, CAR T cells (搜索) no longer improved in response to BHB, confirming that the molecule's benefits depend on direct metabolic use, not just signaling.
Clinical Translation Already Underway
"The findings from this work highlight the potential of simple metabolic intervention for cancer treatment—providing CAR T cells (搜索) with an efficient, naturally occurring fuel source that can meaningfully enhance their performance, even in cancers where current therapies have struggled," says Levy.
A clinical trial of BHB (搜索) supplementation in Large B-cell Lymphoma (搜索) is already underway, suggesting a future in which metabolic supplementation could offer a safe, inexpensive, and accessible strategy to improve T cell function and advance cancer treatment and care. This approach points to the untapped potential of metabolic and lifestyle approaches that are low-cost, scalable, and easily integrated into clinical settings.