Liposome-coated CaO2 nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis

The blocking of the immune checkpoint pathway with antibodies, especially targeting to programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway, was currently a widely used treatment strategy in clinical practice. However, the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1. Herein, we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO2 (CaO2@Lipo) nanoparticles to inhibit the de novo biosynthesis of PD-L1. CaO2@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α (HIF-1α) level, which then downregulated the expression of PD-L1. Our in vitro and in vivo results have confirmed CaO2@Lipo promoted the degradation of HIF-1α and then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape. Furthermore, to mimicking the clinical protocol of anti-PD-L1 antibodies + chemo-drugs, CaO2@Lipo was combined with doxorubicin (DOX) to investigate the tumor inhibition efficiency. We found CaO2@Lipo enhanced DOX-induced immunogenic cell death (ICD) effect, which then promoted the infiltration of T cells, strengthened the blocking effect, and thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.