OVERALL: ABSTRACT This application is a request for renewal funding of the SPORE in Prostate Cancer P50 CA180995 at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in collaboration with the University of Chicago Comprehensive Cancer Center and NorthShore University HealthSystem, an affiliate of the University of Chicago. The SPORE first received support from the National Cancer Institute in 2001; a renewal application was funded in 2009. In 2015, we were the recipients of a new SPORE and we are now requesting continued funding for this program. Our SPORE unites basic scientists, clinicians, pathologists, biostatisticians, bioinformaticists and advocates from our academic institutions, all of whom are dedicated to advancing translational prostate cancer research. In this application we propose three highly translational and innovative research projects that have both basic science and clinical science co-leadership: Project 1: Targeting the MYC Pathway in Prostate Cancer (Abdulkadir, Hussain); Project 2: Re-directing the sensitivity of metastatic castration-resistant prostate cancer to immunotherapy (Wu, Sosman, Morgans); Project 3: STING Activation to Overcome Resistance to Immune Checkpoint Blockade in PTEN-deficient Prostate Cancer (Patnaik, Gajewski, Stadler). Three core facilities support the proposed research projects: Administrative, Leadership and Advocacy (Abdulkadir, Hussain, Stadler); Biostatistics/Bioinformatics (Kocherginsky, Zhao) and Biospecimen (Yang). Internal and External Advisory Boards provide a source of scientific input to members of the SPORE team on a biannual and yearly basis, respectively. Our Advocacy Group are well established in the SPORE arena and make a valued contribution to our success. The SPORE includes Developmental Research and Career Enhancement Programs, both of which provide a source of innovation and new discoveries. All together, we anticipate that the results obtained from our research endeavors will have a significant impact on the health of patients diagnosed with prostate cancer.