Mortezaee Keywan
Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran; Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Pathol Res Pract. 2025 Jun;270:155992. doi: 10.1016/j.prp.2025.155992. Epub 2025 Apr 28.
Enhancer of zeste homolog 2 (EZH2) is a polycomb repressor complex 2 (PRC2) subunit that is responsible for silencing expression of target genes through generation of lysine 27 trimethylation on histone H3 (H3K27Me3). EZH2 is an oncogene aberrantly expressed in human cancers, and its overexpression favors immune escape and metastasis. Immune escape occurs via the impact of EZH2 on hampering antigen expression machinery, stabilizing FOXP3 in regulatory T cells (Tregs), inhibiting recruitment and activity of natural killer (NK) and CD8 T cells, and inducing recruitment and activity of myeloid-derived suppressor cells (MDSCs). Besides, EZH2 also promotes intra-tumoral recruitment of tumor-associated macrophages (TAMs). A point is that pharmacologic EZH2 inhibition (not knockdown) seemingly promotes polarization of macrophages toward pro-tumor M2 phenotype, which defines resistance mechanism. Besides, increased EZH2 expression after anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and a rise in the tumoral expression of programmed death-ligand 1 (PD-L1) after EZH2 inhibition account for secondary immunosuppression in tumor ecosystem after immunotherapy, indicating the applicability of using EZH2 targeted therapies as a combinatory approach with anti-programmed death-1 (PD-1) or anti-CTLA-4 therapy. Such combination reinvigorates anti-tumor immunity and presumably hampers T cell exhaustion and acting as a promising regimen for retarding cancer growth.
zeste同源物2增强子（EZH2）是一种多梳抑制复合物2（PRC2）亚基，负责通过在组蛋白H3上生成赖氨酸27三甲基化（H3K27Me3）来沉默靶基因的表达。EZH2是一种在人类癌症中异常表达的癌基因，其过表达有利于免疫逃逸和转移。免疫逃逸通过EZH2对阻碍抗原表达机制的影响、稳定调节性T细胞（Tregs）中的FOXP3、抑制自然杀伤（NK）细胞和CD8 T细胞的募集及活性以及诱导髓源性抑制细胞（MDSCs）的募集及活性而发生。此外，EZH2还促进肿瘤相关巨噬细胞（TAM）在肿瘤内的募集。关键在于，药理学上抑制EZH2（而非敲低）似乎会促进巨噬细胞向促肿瘤M2表型极化，这确定了耐药机制。此外，抗细胞毒性T淋巴细胞相关抗原4（CTLA-4）后EZH2表达增加以及EZH2抑制后程序性死亡配体1（PD-L1）在肿瘤中的表达升高，说明了免疫治疗后肿瘤生态系统中的继发性免疫抑制，这表明将EZH2靶向治疗作为与抗程序性死亡1（PD-1）或抗CTLA-4治疗联合使用的方法具有适用性。这种联合可恢复抗肿瘤免疫力，并可能阻碍T细胞耗竭，有望成为延缓癌症生长的有效方案。
