The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery

Cell. 2018 Nov 1;175(4):1059-1073.e21. doi: 10.1016/j.cell.2018.08.070. Epub 2018 Sep 27.


Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional "danger sensing." Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation. Additionally, inhibiting the mevalonate pathway enhances antigen-specific anti-tumor immunity, inducing both Th1 and cytolytic T cell responses. As demonstrated in multiple mouse cancer models, the mevalonate pathway inhibitors are robust for cancer vaccinations and synergize with anti-PD-1 antibodies. Our research thus defines the mevalonate pathway as a druggable target for vaccine adjuvants and cancer immunotherapies.

Keywords: bisphosphonate; cancer vaccination; geranylgeranylation; mevalonate pathway; statin; vaccine adjuvant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antigen Presentation
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Diphosphonates / pharmacology*
  • Endosomes / drug effects
  • Female
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Macaca fascicularis
  • Male
  • Mevalonic Acid / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Protein Prenylation
  • rab5 GTP-Binding Proteins / antagonists & inhibitors*
  • rab5 GTP-Binding Proteins / metabolism


  • Adjuvants, Immunologic
  • Cancer Vaccines
  • Diphosphonates
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • rab5 GTP-Binding Proteins
  • Mevalonic Acid