Benefits and Challenges of Inhibiting EZH2 in Malignant Pleural Mesothelioma

Simple Summary Malignant pleural mesothelioma (MPM) is an aggressive cancer linked to asbestos exposure with an extremely poor outcome. Despite the recent approval of immune checkpoint blockade-based therapies, MPM still remains a fatal cancer that challenges physicians and scientists. Enhancer of zeste homolog 2 (EZH2) has emerged as a promising therapeutic target. In addition to being an oncogenic driver, EZH2-dependent epigenetic reprogramming modulates tumor-immune infiltrate. Therefore, we argue that a better understanding of the molecular mechanisms that sensitize cancer cells to EZH2 inhibition and modulate tumor microenvironment will likely provide important insights for new treatment options for MPM. Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer that is mainly associated with prior exposure to asbestos fibers. Despite being a rare cancer, its global rate is increasing and the prognosis remains extremely poor. Over the last two decades, despite the constant research of new therapeutic options, the combination chemotherapy with cisplatin and pemetrexed has remained the only first-line therapy for MPM. The recent approval of immune checkpoint blockade (ICB)-based immunotherapy has opened new promising avenues of research. However, MPM is still a fatal cancer with no effective treatments. Enhancer of zeste homolog 2 (EZH2) is a histone methyl transferase that exerts pro-oncogenic and immunomodulatory activities in a variety of tumors. Accordingly, a growing number of studies indicate that EZH2 is also an oncogenic driver in MPM, but its effects on tumor microenvironments are still largely unexplored. This review describes the state-of-the-art of EZH2 in MPM biology and discusses its potential use both as a diagnostic and therapeutic target. We highlight current gaps of knowledge, the filling of which will likely favor the entry of EZH2 inhibitors within the treatment options for MPM patients.