Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

JCI Insight. 2021 Jan 25;6(2):e145207. doi: 10.1172/jci.insight.145207.


Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.

Keywords: Cancer; Immunotherapy; Metabolism; Mouse models; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / administration & dosage
  • 3-Hydroxybutyric Acid / metabolism
  • Animals
  • CTLA-4 Antigen / antagonists & inhibitors
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Diet, Ketogenic*
  • Female
  • Gastrointestinal Microbiome / immunology
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Ketone Bodies / administration & dosage*
  • Ketone Bodies / metabolism
  • Kidney Neoplasms / diet therapy
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / immunology
  • Melanoma, Experimental / diet therapy
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / diet therapy*
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors


  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Hcar2 protein, mouse
  • Immune Checkpoint Inhibitors
  • Ketone Bodies
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, G-Protein-Coupled
  • 3-Hydroxybutyric Acid