Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model

Cell Chem Biol. 2022 Mar 17;29(3):463-475.e6. doi: 10.1016/j.chembiol.2021.08.001. Epub 2021 Sep 13.


Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of programmed cell death protein 1 (PD-1) blockade, leading to better cancer treatment. Although epigenetic drugs showed potential in combination therapy, the lack of sequence specificity is a major concern. Here, we identify and develop a DNA-based epigenetic activator with tri-arginine vector called EnPGC-1 that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1α/β), a regulator of mitochondrial biogenesis. EnPGC-1 enhances mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhances oxidative phosphorylation, a feature of long-lived memory T cells. Genome-wide gene analysis suggests that EnPGC-1 and not the control compounds can regulate T cell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade to enhance antitumor immunity and improved host survival.

Keywords: PD-1; T-cell activation; cancer immunotherapy; combination therapy; epigenetic activator; mitochondrial biogenesis; oxidative phosphorylation; pyrrole-imidazole polyamide; therapeutic gene modulation.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Epigenesis, Genetic*
  • Mice
  • Mitochondria*
  • Neoplasms* / immunology
  • Organelle Biogenesis*
  • Oxidative Phosphorylation
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors


  • Programmed Cell Death 1 Receptor