Selectively Targeting the TLR9-IRF7 Signaling Pathway By Polymer Blend Particles

Signaling through toll-like receptor 9 (TLR9) has been exploited for cancer therapy.  The stimulation of TLR9 leads to two bifurcating signaling pathways – NF-κB-dependent pro-inflammatory cytokines pathway and IRF-7-dependent type I interferons (IFNs) pathway. In this study, we employ polymer blend particles to present the synthetic ligand, CpG oligonucleotides (CpG ODNs) to TLR9.  The polymer blend particles are made from the blend of a pH-insensitive and pH-sensitive copolymer. By tailoring the composition of the pH-sensitive polymer, CpG ODNs are presented to TLR9 in a way that only activates the IRF-7 signaling pathway.  CpG ODNs have been used for cancer therapy in both preclinical and clinical studies. The selective activation of IRF-7 could potentially enhance the apoptosis of tumor cells and immunological control of tumor progression without inadvertently activating NF-κB-dependent oncogenesis.