The role of EZH2 in malignant pleural mesothelioma and beyond: current practice and future perspectives

Purpose of Review

Malignant pleural mesothelioma (MPM) remains a rare but highly aggressive malignancy with limited treatment options and poor prognosis. For nearly twenty years, platinum–pemetrexed chemotherapy has persisted as the unchanged standard treatment; although recent progress in immunotherapy has modestly disrupted this therapeutic plateau, survival outcomes remain disappointingly limited. This review aims to provide a comprehensive overview of the epigenetic landscape of MPM, focusing particularly on the oncogenic and therapeutic implications of enhancer of zeste homolog 2 (EZH2), and to discuss its potential as a target for novel therapeutic strategies and combination regimens.

Recent Findings

Epigenetic dysregulation has emerged as a central driver of mesothelioma pathogenesis. EZH2, the catalytic component of the polycomb repressive complex 2 (PRC2), mediates histone H3K27 trimethylation, silencing tumor suppressor genes and promoting malignant transformation. In addition to its canonical role, EZH2 has non-canonical oncogenic effects that modulate transcription, apoptosis, DNA repair, and immune evasion. High EZH2 expression correlates with BAP1 loss, which enhances chromatin remodeling defects and disease aggressiveness. Preclinical and early clinical data demonstrate that EZH2 inhibitors—including tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, and novel PROTAC-based degraders such as MS1943—can suppress tumor progression, modulate the tumor immune microenvironment, and restore therapeutic sensitivity. Furthermore, combination approaches integrating EZH2 inhibition with chemotherapy or immune checkpoint blockade show synergistic potential in overcoming resistance.

Summary

EZH2 represents a pivotal epigenetic regulator and a promising therapeutic target in MPM. Further understanding the dual canonical and non-canonical roles of EZH2 in tumor biology will be key to optimizing targeted and combinatorial treatment strategies. Future research should focus on translating EZH2 inhibition into clinical benefit, identifying predictive biomarkers of response, and exploring rational combinations with chemotherapy, targeted drugs, or immunotherapy to improve survival outcomes in mesothelioma patients.