Advancing Cancer Immunotherapy through Engineering New PD-L1 Degraders: A Comprehensive Study from Small Molecules to PD-L1-Specific Peptide–Drug Conjugates

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