Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in men older than 40 years in the United States. PCa is a significant health concern particularly in patients who are resistant to standard hormone therapies, such as androgen deprivation. These patients have developed castration-resistant prostate cancer (CRPC), which has a median survival rate of only 14-15 months, thus the development of novel therapeutic targets is critical. It is known that the host’s immune system can often recognize cancerous cells and destroy these transformed cells. One of the earliest pathways in immune activation is the presentation of lipid antigens by CD1d molecules to a unique subpopulation of T cells called natural killer T (NKT) cells. NKT cells are primed cells which can, if appropriately activated, lead to the development of a robust anti-tumor immune response. However, the immune system in PCa may be compromised as we and others have observed a profound reduction in circulating NKT cells in the blood of PCa patients. Studies in our lab have further demonstrated that blockade of sphingosine kinase, a key regulator in cellular metabolism, can restore NKT cell responses to tumor cells by modulating CD1d-mediated antigen presentation. Therefore, we hypothesize that therapeutic approaches that target lipid metabolism in combination with NKT cell-based immunotherapy will effectively target tumor and supporting stromal cells within the tumor microenvironment.