A naturally occurring byproduct of liver metabolism–the ketone body, β-hydroxybutyrate (BHB)–can strengthen the fitness and antitumor activity of CAR T cells. The findings, reported on March 6, 2026 in the journal Cell , by Arc Institute and Stanford University scientists, together with colleagues from the University of Pennsylvania, highlight a potential new way to enhance cancer immunotherapies. The team, led by Maayan Levy, demonstrated that BHB—a metabolite produced after prolonged fasting or when on a ketogenic diet—can act as a powerful fuel source for T cells used in immunotherapy. BHB was found to reshape both T cell energy production and gene regulation in ways that improve tumor control across multiple cancer models.
“CAR T cell therapy has revolutionized treatment for certain blood cancers, yet many patients still fail to respond or eventually relapse,” says Levy (X: @MaayanLevyPhD ), an Assistant Professor of Pathology at Stanford and an Arc Innovation Investigator in Residence. “This challenge has led scientists to search for new, practical ways to strengthen T cell metabolism, without presenting additional burdens on patients.”
Levy's team 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. Of these, only the ketogenic diet showed consistently improved tumor control following CAR T therapy. To understand this effect, the researchers examined metabolic differences and found that ketogenic-fed mice had higher levels of BHB relative to all other groups, pointing to BHB as the defining metabolic difference among the keto-fed mice.
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. Because of these challenges, the team explored whether BHB supplementation alone could provide the same benefit. Across several cancer models, including lymphoma, leukemia, and even a notoriously resistant pancreatic cancer 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––BHB 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.”
To better understand why BHB is so effective, the team looked at how it affects T cell metabolism. Using stable isotope tracing, they tracked how CAR T cells used BHB as fuel and found that the cells rapidly incorporated it into the TCA cycle, the central pathway that powers mitochondria, helping the cells create more usable energy and withstand the stress of fighting cancer. Further tests also confirmed that BHB-exposed CAR T cells consumed more oxygen and produced more ATP, a key energy molecule, than standard CAR T cells.
Using single-cell RNA sequencing, the team also found that BHB-treated CAR T cells 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, tools that show which parts of a cell’s DNA are active, revealed 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.
Finally, to test whether T cells need to metabolize BHB for it to aid CAR T cell therapy, the researchers used CRISPR to knock out BDH1, the enzyme that converts BHB into usable energy. Without BDH1, CAR T cells no longer improved in response to BHB, confirming that the molecule’s benefits depend on direct metabolic use, not just signaling.
“The findings from this work highlight the potential of simple metabolic intervention for cancer treatment––providing CAR T cells with an efficient, naturally occurring fuel source that can meaningfully enhance their performance, even in cancers where current therapies have struggled,” says Levy.
While genetic engineering remains an important avenue for cancer research and treatment, this study points to the untapped potential of metabolic and lifestyle approaches that are low-cost, scalable, and easily integrated into clinical settings. With a clinical trial of BHB supplementation in Large B-cell Lymphoma already underway, this work suggests 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.
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To learn more about how this study fits into the broader scientific vision of the Levy Lab, read a Q&A with Maayan Levy .
Liu, S., Guruprasad, P., Ramasubramanian, R., Madhu, B., Paruzzo, L., Han, K., Kelly, A., Shestov, A., Xu, H.N., Carturan, A., Zhou, C., Amses, K.R., Afriat, A., Litichevskiy, L., Lin, J., Dubowitz, E., Tangal, N., Zhang, J., McSween, A., Tan, M., Stella, F., Lee, A., Nason, S., Hua, X., Schneider, M., Sleeman, M., Zhang, Y., Gabrielli, G., Yang, Z., Pajarillo, R., Patel, R., Ghilardi, G., Patel, V., Joshi, A., Jiang, S., Jiang, Y., Porazzi, P., Tchou, J.C., Keith, B., Li, M., Chong, E., Schuster, S.J., Milone, M., Rabinowitz, J., O'Connor, R., Thaiss, C.A., Levy, M., & Ruella, M. (2026). β-Hydroxybutyrate Enhances the Metabolic Fitness of CAR T Cells in Cancer. Cell . https://doi.org/10.1016/j.cell.2026.02.004
Arc Institute (X: @arcinstitute ) is an independent nonprofit research organization based in Palo Alto, California, that aims to accelerate scientific progress and understand the root causes of complex diseases. Arc's investigators are supported by long-term funding and freedom to pursue bold ideas. Its Technology Centers leverage multi-omics, genome engineering, and cellular, mammalian and computational models to advance discoveries at the intersection of biology and artificial intelligence. Founded in 2021, Arc partners with Stanford, UC Berkeley, and UCSF.
Cell
Experimental study
Animals
β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer
6-Mar-2026
Funding information and declarations of interest can be found in the published paper.