The Complex Role of EZH2 in the Tumor Microenvironment: Opportunities and Challenges for Immunotherapy Combinations

Immune dysfunction in the tumor microenvironment occurs through epigenetic changes in both tumor cells and immune cells that alter transcriptional programs driving cell fate and cell function. Oncogenic activation of the histone methyltransferase EZH2 mediates gene expression changes, governing tumor immunogenicity as well as differentiation, survival and activation states of immune lineages. Emerging preclinical studies have highlighted the potential for EZH2 inhibitors to reverse epigenetic immune suppression in tumors and combine with immune checkpoint therapies. However, EZH2 activity is essential for the development of lymphoid cells, performing critical immune effector functions within tumors. In this review, we highlight the complexity of EZH2 function in immune regulation which may impact the implementation of combination with immunotherapy agents in clinic.