Advances in cancer immunotherapy using small-molecular inhibitors targeting the PD-1/PD-L1 interaction.

Cancer cells evade immune responses by interacting with PD-1 and its ligand, PD-L1. Although monoclonal antibodies targeting this pathway have revolutionized oncology, their high production costs, poor oral bioavailability, and limited tumor penetration remain significant challenges. Small-molecule inhibitors provide a promising alternative, offering advantages such as improved tumor penetration and cost-effectiveness. This review highlights advancements in small-molecule PD-1/PD-L1 inhibitors, focusing on their mechanisms, structural designs, and therapeutic potential. Key innovations, including biphenyl scaffolds, heterocyclic frameworks, enhance binding efficiency and immune activation. The article effectively integrates fundamental principles of drug chemistry with real-world clinical needs, offering a comprehensive approach to the design of PD-1/PD-L1 small-molecule inhibitors. It systematically classifies various molecular structures, analyzes relevant industrial cases, and incorporates the most recent research findings. By examining these aspects, it uncovers the underlying logic driving the design process and provides a fresh, innovative perspective on advancing the field of immune small-molecule inhibitors for cancer therapy.