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PD-1/PD-L1 pathway, a key immune checkpoint, triggers T-cell exhaustion via binding and aiding tumor immune evasion. Although several anti-PD-1/PD-L1 monoclonal antibodies (mAbs) have been granted food and drug administration (FDA) approval, their high cost, poor oral bioavailability, and potential immunogenicity have led to a shift in research toward small molecules. This review summarizes the structure and function of PD-1/PD-L1 and, based on the PD-1/PD-L1 signaling process, focuses on three major classes of related compounds: small molecule inhibitors inducing PD-L1 dimerization or blocking PD-1/PD-L1 binding; PD-L1 degraders (e.g., Proteolysis-targeting chimeras (PROTACs) and Lysosome-targeting chimeras (LYTACs)) via the ubiquitin-proteasome or lysosomal pathway, overcoming membrane protein targeting; and dual-target inhibitors that enhance therapeutic efficacy by exerting synergistic effects. While small molecule drugs have advantages over monoclonal antibodies, including oral administration and reduced immunogenicity, they face drug resistance and toxicity challenges. This review aims to provide insights into the discovery of safe and effective antitumor immunotherapeutic agents.