The development of novel and efficient therapies for metastatic prostate cancer (PCa) is an urgent need. A main challenge in this development is the concomitant targeting of alterations to PCa cells (e.g. neuroendocrine trans-differentiation) and the accumulation of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment. This accumulation inhibits Tcell responses and decreases anti-tumor immunity. This challenge is further enhanced by the chemo-resistance of neuroendocrine prostate cancer cells (NEPC). To confront such challenge, we propose a synergistic collaboration that combines two novel therapeutic modalities (i) Oncolytic virotherapy which employs oncolytic viruses to directly kill cancer cells and elicit anti-tumor immunity; and (ii) therapeutic oligonucleotides, which concomitantly reduce the tumorigenic potential of PCa cells and enhance anti-tumor immunity through specific targeting of the expression of signaling regulators in tumor- and myeloid-derived suppressor cells. We will employ EHDV-TAU, a novel oncolytic orbivirus developed by the Ehrlich and Bacharach labs, which explores cancer-induced defects to the innate-immune antiviral responses to target PCa cells, and CpG-conjugated oligodeoxynucleotides (ODN) or siRNA, developed by the Kortylewski lab, to specifically silence STAT3 and/or STAT1 in TLR9+ myeloid and PCa cells.