Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

Cancer Cell. 2016 Jul 11;30(1):147-160. doi: 10.1016/j.ccell.2016.05.016.


Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

Keywords: cancer; chemotherapy; immunosurveillance; regulatory T cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Autophagy-Related Protein 5 / genetics
  • Caloric Restriction / methods
  • Cell Line, Tumor
  • Citrates / administration & dosage*
  • Citrates / pharmacology
  • Humans
  • Methotrexate / administration & dosage
  • Methotrexate / pharmacology
  • Mice
  • Monitoring, Immunologic
  • Mutation
  • Neoplasm Transplantation
  • Neoplasms, Experimental / diet therapy*
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / immunology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Spermidine / administration & dosage*
  • Spermidine / pharmacology
  • T-Lymphocytes, Regulatory / drug effects*


  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Citrates
  • hydroxycitric acid
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Spermidine
  • Methotrexate