Research Progress and Clinical Translation Challenges of Small‐Molecule Inhibitors Targeting PD‐L1

Abstract

Antibody-based drugs targeting the PD-1/PD-L1 axis have become widely used in clinical treatments. However, challenges such as high costs and suboptimal clinical response rates have fueled growing interest in developing small-molecule inhibitors. Recent clinical trials, both domestically and internationally, have evaluated several small-molecule inhibitors. Notable compounds like CA-170 and INCB086550 have shown promising properties and potential in these studies. Although no small-molecule inhibitors targeting PD-L1 have yet been approved for clinical use, the path to their development and clinical translation is fraught with challenges. Researchers are actively exploring innovative strategies for drug design and synthesis, while carefully assessing critical factors such as safety and efficacy. Given the essential role of the PD-1/PD-L1 pathway in immune evasion by tumors, this review provides a concise overview of the signaling and structure of PD-1/PD-L1, summarizes current progress on clinical candidate drugs targeting this pathway, discusses the challenges in translating small-molecule inhibitors to clinical practice, and outlines future directions in drug development.