Prostate cancer is associated with an immunosuppressive tumor microenvironment, including relatively low tumor mutational burden (TMB), increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. As a result, immuno-oncology approaches for the treatment of metastatic prostate cancer have previously met with limited success. Sipuleucel-T, an autologous cellular immunotherapy designed to induce immune responses against prostatic acid phosphatase (PAP), is the only immuno-oncology agent approved by the U.S. Food and Drug Administration (FDA) for prostate cancer, other than pembrolizumab which is now FDA-approved for treatment of all microsatellite instability (MSI)-high and TMB-high advanced solid tumors. However, sipuleucel-T has a short window for optimal clinical use, being best administered as first-line treatment for selected patients with metastatic castration-resistant prostate cancer and indolent disease. Studies are ongoing investigating the use of sipuleucel-T in earlier stages of prostate cancer, as well as in combination with other therapies.