Small Molecules, Big Impact: Structural Innovations Driving PD-L1 Checkpoint Modulation

Cancer immunotherapy enhances the body's ability to recognize and eliminate tumor cells, mainly by modulating immune checkpoints such as PD-1/PD-L1 and CTLA-4. Monoclonal antibody inhibitors targeting PD-1 or PD-L1 have transformed cancer care, but their high cost, IV administration, and immune-related toxicities have encouraged the development of small-molecule alternatives. Early PD-L1 small-molecule inhibitors, pioneered by Bristol Myers Squibb, block PD-1/PD-L1 interactions by occupying hydrophobic pockets on PD-L1, and SAR studies continue to refine their potency and selectivity. This review focuses on how the structural scaffolds of small-molecule PD-L1 inhibitors determine their mechanisms of action, protein interactions, and biological performance. We examine how different chemotypes influence dimerization of PD-L1, disruption of PD-1 binding, or engagement of additional immune-modulatory pathways. Special attention is given to scaffolds capable of acting through more than one mechanism, as these may offer broader or more durable immunomodulatory effects. We also compare how scaffold design correlates with activity across in vitro assays, co-culture immune models, and in vivo tumor systems, highlighting the physicochemical features that enable or limit translatability. Finally, we discuss emerging clinical efforts, the challenges underlying trial failures, and how refined structural design may guide the next generation of small-molecule PD-L1 inhibitors.