Prostate cancers have proven resilient to emerging clinical immunotherapies, including cancer vaccines and immune checkpoint blockade. Growing evidence emphasizes the role of the tolerogenic tumor microenvironment, with the essential role of STAT3 signaling in myeloid cells, in shielding prostate cancers from antitumor immunity. Here, we describe new bifunctional CpG-STAT3ASO molecules, which trigger Toll-like Receptor 9 (TLR9) immunostimulation while eliminating negative effect of STAT3. Despite known challenges in penetrating solid tumors by intravenously injected oligonucleotides, CpG-STAT3ASO effectively targeted TLR9+ myeloid cells in bone-localized prostate tumors, resulting in immune-mediated eradication of tumors regardless of their genetic background. Our study highlights the potential of using a CpG-ASO strategy to target other “undruggable” master regulators of tumorigenic functions of myeloid cells. We believe that these findings, underscored by the ongoing investigational new drug (IND)–enabling studies of first-generation CpG-STAT3 inhibitors, have broad implications for the design of oligonucleotide strategies for prostate cancer immunotherapy.