Research Progress in Bifunctional small molecules for cancer immunotherapy

Abstract

Immunotherapy has become one of the most revolutionary modalities for cancer treatment with the approval of many anti-PD-L1 (programmed cell death-ligand 1) /PD-1 (programmed cell death-1) monoclonal antibodies (mAbs). However, anti-PD-L1/PD-1 mAbs suffer from several drawbacks including limited clinical efficacy (∼20%), poor pharmacokinetics, and the development of immune resistance. Hence, the search for PD-1/PD-L1-based combination therapies and other PD-L1-based bifunctional small molecule modulators [e.g. PD-L1/HDAC (Histone Deacetylase), PD-L1/CXCL12 (C-X-C chemokine ligand 12), PD-L1/Tubulin, PD-L1/IDO1 (Indoleamine 2,3 dioxygenase 1), PD-L1/PARP (Poly(ADP-ribose) polymerase), PD-L1/STING (Stimulator of interferon genes), and PD-L1/NAMPT (Nicotinamide phosphoribosyltransferase)-targeting dual inhibitors] has been intensified with considerable strides achieved in the past couple of years. Herein, we summarize the latest development of bifunctional small molecules as immunotherapy for tumor treatment, including those PD-L1-based, A_2AR (Adenosine 2A receptor)-based, IDO1-based, Toll-like receptor (TLR)-based, SHP2 (Src homology 2 domain-containing phosphatase 2)-based, and HPK1 (Hematopoietic progenitor kinase 1)-based dual-acting compounds. In addition, we also summarize the tumorigenesis and synergy mechanism of various targets. Finally, the challenges and future directions for bifunctional small molecules for cancer immunotherapy are also discussed in detail.