In this study, we explored a strategy of linking siRNAs to synthetic oligonucleotide agonists for endosomal TLRs, which include TLR3, TLR7, TLR8 and TLR9 26 , 27 , 28 , for targeted delivery of siRNA into immune cells, together with TLR-dependent activation of antitumor immune responses. The endosomal location of the oligonucleotide-binding TLRs might be advantageous in facilitating the siRNA component to reach the cytosol for efficient gene silencing in cells selectively expressing the cognate TLR. In order to model this concept, we chose TLR9-specific oligodeoxynucleotides containing an unmethylated CpG-motif (CpG ODN), because they are already in clinical testing 29 . Additionally, CpG ODNs are efficiently internalized by various antigen-presenting cells, such as dendritic cells (DCs), macrophages and B cells, and their binding to TLR9 can initiate a cascade of innate and adaptive immune responses 30 , 28 , 29 . Myeloid cells and B cells are also critical components of the tumor microenvironment that actively promote oncogenesis 12 , 17 , 19 , 21 , 22 . By linking the  single-stranded CpG ODN with double-stranded siRNA, we have created a single synthetic  molecule capable of delivering siRNA into myeloid and B cells, silencing an immune  checkpoint and/or oncogenic gene, and activating TLR, leading to therapeutic antitumor  immune responses. 