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

Abstract

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+ Tcells invitro, and, in particular, enhances oxidative phosphorylation, a feature of long-lived memory Tcells. Genome-wide gene analysis suggests that EnPGC-1 and not the control compounds can regulate Tcell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade to enhance antitumor immunity and improved host survival.