Metastatic castration-resistant prostate cancer (mCRPC) is currently incurable. When diagnosed at early stages, prostate cancer is very treatable with surgery, radiation, and androgen deprivation (ADT) therapy. Within years, patient tumors will become resistant to ADT and eventually spread becoming metastatic. Current treatment options for mCRPC are available, but more as palliative care to increase the quality of life of these affected patients with minor improvement to overall survival. New therapeutic approaches are needed, to not only improve the survival of such patients, but to also find more aggressive therapy options for high risk populations that have higher tumor growth rates, larger tumor volumes, and higher mortality rates. Here, we present a therapeutic option that uses TNF-related apoptosis inducing ligand (TRAIL) on nanoscale liposomes, along with current FDA-approved chemotherapies, docetaxel and cabazitaxel, to treat models of mCRPC. Th scope of the work presented includes: (1) An investigation of the spatial density of leukocytes armed with TRAIL that infiltrate and treat primary prostate tumors, (2) an investigation of TRAIL-sensitization mechanisms in TRAIL-resistant cell lines using taxane therapy in 2D cell culture, and (3) an evaluation of overcoming TRAIL-resistance via taxane exposure using 3D spheroids.