Tumor immunotherapy is revolutionizing the treatment approach for cancer, and has significantly improved overall survival and progression-free survival in various types of cancer patients. The mechanism of action for immune checkpoint inhibitors involves blocking the interaction between programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), thereby reactivating the anti-cancer activity of cytotoxic T cells and exerting an immune-mediated anti-cancer effect. However, the PD-1/PD-L1 monoclonal antibody has a clinical efficacy rate of only about 10%-30%, and can also cause severe treatment-related adverse reactions such as immune myocarditis. Small molecule compounds have several advantages in terms of pharmacokinetics, such as better oral bioavailability, higher penetration into relevant tissues and tumor cells, and reasonable half-life. Currently, the development of small-molecule tumor immunotherapeutic drugs has become a highly active research field in cancer immunotherapy. This article aims to summarize the recent advancements in small molecule research for tumor immunotherapy over the past five years, including PD-L1 small molecule inhibitors, PD-L1 degraders based on proteolysis-targeting chimeras, and lysosome-targeting chimeras technologies, and discuss the future directions for the development of small molecule inhibitors, providing new theoretical references for tumor immunotherapy.

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