Prostate cancer (CaP) is the most commonly diagnosed cancer and the second leading cause of cancer death in men over the age of fifty. Bone is the primary site of metastasis in patients whose CaP progresses beyond organ confinement. The absence of curative therapies for metastatic CaP emphasizes the imperative to develop innovative technologies for target-specific delivery of therapeutic agents as well as novel treatment strategies that are efficacious with minimal toxicity. Our investigative team seeks to address different aspects of CaP bone metastasis through a highly integrated and focused research effort that will enhance our comprehension of the mechanisms underlying CaP progression and improve therapeutic strategies to eradicate bone metastases and prevent relapse. Our early work using a subtraction hybridization screen identified two unique genes, i.e., melanoma differentiation associated gene-9 (mda-9) and mda-7/IL-24 from terminally differentiating human melanoma cells. Subsequent research established MDA-9 as a key promoter of cancer invasion and metastasis, whereas MDA-7/IL-24 was recognized as a broad-spectrum anti-cancer therapeutic. Using a newly developed syngeneic pre-clinical model of CaP bone metastasis, we will investigate the interplay between CaP bone metastases and the bone niche orchestrated by MDA-9 and evaluate therapeutic activity of ‘first-in-class’ small molecule inhibitor of MDA-9 (i.e., PDZ1i) for targeting both metastatic CaP cells and the bone niche. By exploiting the exquisite ability and high efficiency of T cells to locate and destroy disseminated cancer cells, especially those in normally inaccessible sites, i.e., bone, we will engineer CaP-reactive T cells to produce MDA-7/IL-24, a unique cancer-selective apoptosis-inducing cytokine, for improved capacity to attack potentially antigenically heterogenous bone metastases. Last, based on the ability of PDZ1i to reprogram the immune niche in the tumor microenvironment, we will combine engineered T cells producing next-generation MDA-7/IL-24 (“Superkine MDA-7/IL-24“, “S7M”), having enhanced secretion and stability, with MDA-9-targeted therapy for synergistic elimination of CaP bone lesions. We anticipate that the insights garnered from these studies will enable a more precise molecular understanding of bone metastasis development for target discovery, rational design of improved cellular immunotherapy, and combinatorial treatment modalities optimized to achieve a maximum therapeutic potential. Successful completion of this multidisciplinary, synergistic research program will provide a rapid path to translate these technologies and strategies into the clinic to safely and effectively manage this most common skeletal complication of CaP.