Despite the initial efficacy of hormone therapies, prostate tumors eventually progress to metastatic castration-resistant prostate cancers (mCRPC), which resist current therapies and also the emerging immunotherapeutic regimens. The advanced prostate cancers develop a potently immunosuppressive microenvironment which partly relies on the heterogeneous population of myeloid-derived suppressor cells (MDSC). We identified a specific population of granulocytic MDSCs that accumulated in patients’ circulation during prostate cancer progression from localized to metastatic disease. These TLR9+ MDSCs showed high levels of immunosuppressive mediators, STAT3 and Arginase-1, and inhibited effector T-cell proliferation and activity. Targeting MDSCs using CpG-STAT3siRNA strategy alleviated their immunosuppressive functions, restoring T-cell activity. With the ongoing clinical translation of CpG-STAT3siRNA conjugates to therapy of hematologic malignancies, our results underscore the potential of utilizing these oligonucleotide reagents to immunotherapy of advanced prostate cancers.