EZH2 at the epigenetic–immune interface: a dual-axis framework for tumor immune evasion and precision combination immunotherapy

Despite the transformative activity of immune checkpoint blockade (ICB) and adoptive cellular therapies in selected malignancies, durable responses remain limited in many solid tumors, in part because tumor-intrinsic and microenvironmental epigenetic programs can restrict immune recognition and antitumor effector function. Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of polycomb repressive complex 2 (PRC2), contributes to this regulation through canonical H3K27 trimethylation-dependent repression, as well as context-dependent functions that extend beyond a simple model of uniform immune suppression. We organize the available evidence into a dual-axis framework in which tumor-intrinsic EZH2/PRC2 activity can regulate major histocompatibility complex class I and II antigen presentation, interferon and viral-mimicry programs, programmed death-ligand 1 (PD-L1), and T helper 1 (TH1)-type chemokines, whereas tumor-extrinsic EZH2 activity influences macrophages, regulatory T cells, CD8 + T cells, and natural killer (NK) cells. Importantly, these effects are not uniformly immunostimulatory: systemic or prolonged EZH2 perturbation has also been associated with myeloid-derived suppressor cell (MDSC) expansion in selected preclinical settings. Early-phase human studies established the feasibility, but not the incremental clinical benefit, of combining tazemetostat with programmed cell death protein 1 (PD-1)/PD-L1 blockade or chimeric antigen receptor (CAR) T-cell therapy; its subsequent withdrawal after a hematologic safety signal leaves further clinical testing of this strategy to other EZH2- or EZH1/EZH2-directed agents. These observations support mechanism-matched, biomarker-informed, compartment-aware, and temporally controlled EZH2 modulation rather than indiscriminate systemic EZH2 inhibition as the more appropriate framework for future immunotherapy combinations.