Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

SIMPLE SUMMARY: In recent years, therapeutic options for patients with metastatic prostate cancer have improved significantly. However, the efficacy of current immunotherapy strategies in metastatic prostate cancer patients is limited. The prostate cancer tumor microenvironment, which includes immunosupressive cells such as tumor-associated macrophages, has been proposed as a major barrier to the effectiveness of immunotherapy. Thus, macrophages have emerged as a promising target to directly reduce tumor progression and overcome immunotherapy resistance. In this review we will summarize the current status of therapies targeting macrophages as well as their potential to increase immunotherapy efficacy in metastatic prostate cancer. ABSTRACT: Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.