PD-L1 small-molecule modulators: a new hope in epigenetic-based multidrug cancer therapy?

Programmed death-ligand 1 (PD-L1) is an immune checkpoint protein the overexpression of which results in an inhibitory signal that induces T cell exhaustion responsible for immune escape in tumors. Immunotherapy strategies targeting the PD-L1 pathway have achieved remarkable success in treating various types of cancer. More recently, numerous advances in understanding the complex PD-L1 biology have been made, and the first small-molecule inhibitors have been described in the literature. In this review, we highlight the most promising recent advances in understanding the complex regulation mechanisms focusing on small-molecule modulators, which could be used in rational therapy combinations with other epigenetic chemotherapeutic agents. Teaser This article reviews the latest findings regarding PD-L1 immunotherapy related to epigenetically influenced pathophysiological conditions and the state of the art in drug design of PD-L1-targeting agents and combinatory therapies.