A tumor extracellular pH-sensitive PD-L1 binding peptide nanoparticle for chemo-immunotherapy of cancer

Chemo-immunotherapy is a promising model for the combination treatment of cancer. Many solid tumors overexpress programmed cell death ligand (PD-L1) for immune suppression. In this study, a PD-L1 binding peptide conjugate (DCS) nanoparticle with tumor extracellular pH-responsiveness was developed for efficient chemo-immunotherapy of colon cancer. A hydrophilic D-type polypeptide (D-PPA) and two hydrophobic stearyl chains were linked with a pH-sensitive linker to obtain amphiphilic DCS, which could self-assemble into nanoparticles (NPs). Anticancer agent doxorubicin (DOX) was loaded to obtain DOX@DCS NPs, which could accumulate at the tumor site by enhanced permeability and retention effect and release D-PPA at tumor extracellular pH. The release of D-PPA could not only lead to instability and aggregation of NPs for enhanced tumor retention but also block PD-1/PD-L1 to avoid immune escape and elicit enhanced immune response. In addition, DOX could induce immunogenic cell death (ICD) of cancer cells and promote anti-tumor immune response with the combination of PD-1/PD-L1 blocking. DOX@DCS showed efficient inhibition of CT26 tumors and induced immune response both in vitro and in vivo. Overall, our study reported a facile yet robust nanosystem based on an immune blocking peptide and a chemotherapeutic ICD inducer for efficient chemo-immunotherapy of cancer.