Abstract
Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a major cause of cancer-related deaths. Whereas localized PCa can be cured by surgery and radiotherapy, metastatic disease can be treated, but is not curable. Inhibition of androgen signaling remains the main therapeutic intervention for treatment of metastatic PCa, in addition to chemotherapy, radionuclide therapy and emerging targeted therapies. Although initial responses are favorable, resistance to these therapies invariably arise with development of castration resistant PCa (CRPC) and lethal phenotypes. Recent findings have implicated the crosstalk between PCa cells and the tumor microenvironment (TME) as a key factor for disease progression and metastasis, and the immune system is becoming an increasingly attractive target for therapy. Given the striking success of immune checkpoint inhibitors (ICIs) in various cancer types, preclinical and clinical studies have begun to explore their potential in PCa. It has become clear that the PCa TME is largely immunosuppressive, and ICI therapy does not have efficacy for PCa. Intense effort is therefore being made in the field to understand the mechanisms of suppression and to turn the immunosuppressive TME into an immune active one that would enable ICI efficacy. Herein we examine this recent body of knowledge and how the mutational landscape of PCa integrates with an immunosuppressive TME to circumvent ICI-mediated T-cell activity and tumor killing. We then review the emerging potential success of combinatorial ICI approaches, utility of careful patient selection, and potential novel strategies to improve the efficacy of ICI for PCa therapy.