β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer

Shan Liu1,2,3,4,13 ∙ Puneeth Guruprasad1,2,3,13 ∙ Ranjani Ramasubramanian1,2,3,14 ∙ … ∙ Christoph A. Thaiss6,7 ∙ Maayan Levy6,7,15 levym@stanford.edu ∙ Marco Ruella1,2,3,15,1

Highlights

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BHB boosts CAR T cell metabolism to achieve tumor control

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BHB drives TCA cycle, powering CAR T cells

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Human data show BHB boosts peripheral T cell metabolism in volunteers

Summary

The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.

https://www.cell.com/cell/abstract/S0092-8674(26)00169-8