• PD-1/PD-L1 immune checkpoint is a key mediator of tumor immune escape, and posttranslational modifications (PTMs) critically regulate PD-L1 stability and function.
• Small-molecule compounds that modulate PD-L1 PTMs offer a promising alternative to monoclonal antibody immunotherapies, overcoming limitations such as poor oral bioavailability and high cost.
• The review highlights specific PTMs (e.g., ubiquitination, glycosylation, phosphorylation) and small-molecule examples that promote PD-L1 degradation, thereby enhancing antitumor immunity.
• Targeting PD-L1 PTMs with small molecules represents a novel therapeutic strategy with potential to improve clinical outcomes in cancer patients.