Advancing Cancer\nImmunotherapy through Engineering\nNew PD-L1 Degraders: A Comprehensive Study from Small Molecules to\nPD-L1-Specific Peptide–Drug Conjugates

Despite the considerable achievements of antibodies targeting\nPD-1/PD-L1\nin cancer immunotherapy, limitations in antitumor immune response\nand pharmacokinetics hinder their clinical adoption. Small molecules\ntoward PD-L1 degradation signifies an innovative avenue to modulate\nPD-1/PD-L1 axis. Herein, we unveil a comprehensive engineering involving\nthe development of new PD-L1 degraders based on the berberine (BBR)\nand palmatine (PMT) bioactive frameworks and explore their translational\npotential for cancer immunotherapy using a peptide-drug conjugate\nstrategy. Chemical modifications at the O-9 position of PMT dramatically\nenhance the PD-L1 degradation capacity. Further conjugation of PMT\ndegraders with an anti-PD-L1 peptide featuring disulfide linkers enables\nefficient GSH-specific prodrug activation, yielding synergistic immunotherapeutic\nbenefits through both external PD-L1 blockade and internal PD-L1 degradation\nmechanisms. This work elucidates the compelling charm of the discovery\nand application of PD-L1 degraders, offering solutions to the challenges\nin advancing cancer immunotherapy in widespread clinics.