Advancing cancer immunotherapy: Small-Molecule, biomacromolecular, and nanoscale PROTACs targeting PD-L1 for degradation

Le résumé fourni par la source

Programmed death-ligand 1 (PD-L1) is a key immune checkpoint protein that enables tumor immune evasion by engaging PD-1 on T cells, thereby inhibiting their cytotoxic function. Although immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have marked a breakthrough in cancer therapy, their effectiveness is often hampered by acquired resistance and immune-related adverse effects. Proteolysis-targeting chimeras (PROTACs) present a transformative approach by catalytically degrading PD-L1 instead of merely blocking its interaction with PD-1, offering a promising strategy to circumvent resistance and amplify therapeutic efficacy. This review systematically examines recent advancements in PD-L1-targeting PROTACs, including small-molecule PROTACs, biomacromolecule PROTACs, and nano-PROTACs, covering molecular design principles, mechanistic underpinnings, and preclinical validation. We also discussed how PD-L1 degradation can improve immunotherapy by regulating the tumor microenvironment (TME) and enhancing T-cell-mediated cytotoxicity. By synthesizing these insights, this review provides a roadmap for developing next-generation precision immunotherapies leveraging targeted protein degradation.

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