Bifunctional small molecules targeting PD-L1/CXCL12 as dual immunotherapy for cancer treatment

Dear Editor,Inhibiting PD-1/PD-L1 interaction is a highly promising therapeutic modality.1 However,due to the low overall response rate in patients,researchers have attempted to combine PD-L1 inhibitors with other antitumor agents for cancer therapy.Studies have shown that combination immunotherapy of PD-L1 antibodies with CXCL12 inhibitors exhibited synergistic and better antitumor efficacy than monotherapy,indicating the potential clinical utility of targeting both PD-L1 and CXCL12 as dual immunotherapy to treat cancer.2,3 However,there are several disadvantages for combination therapy,including unpredictable PK/PD and overlapping toxicities.A potential alternative to combination therapy would be to use a single molecule with dual or multi-targeting capability,as the PK/PD of a single molecule is easily predictable.For example,dual-targeting bispecific antibodies(bsAbs)have gained significant attention in the field of anticancer drug discovery in recent years.Many PD-1/PD-L1-based bsAbs(e.g.,anti-PD-L1/TGF-β,anti-PD-1/CTLA-4,and anti-PD-1/LAG-3)have entered clinical trials as dual immunotherapy for treating cancer.