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Enhancer of zeste homolog 2 (EZH2) is a significant epigenetic regulator that plays a critical role in the development and progression of cancer. However, the multiomics features and immunological effects of EZH2 in pan-cancer remain unclear. Transcriptome and clinical raw data of pan-cancer samples were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and subsequent data analyses were conducted by using R software (version 4.1.0). Furthermore, numerous bioinformatics analysis databases also reapplied to comprehensively explore and elucidate the oncogenic mechanism and therapeutic potential of EZH2 from pan-cancer insight. Finally, quantitative reverse transcription polymerase chain reaction and immunohistochemical assays were performed to verify the differential expression of EZH2 gene in various cancers at the mRNA and protein levels. EZH2 was widely expressed in multiple normal and tumor tissues, predominantly located in the nucleoplasm. Compared with matched normal tissues, EZH2 was aberrantly expressed in most cancers either at the mRNA or protein level, which might be caused by genetic mutations, DNA methylation, and protein phosphorylation. Additionally, EZH2 expression was correlated with clinical prognosis, and its up-regulation usually indicated poor survival outcomes in cancer patients. Subsequent analysis revealed that EZH2 could promote tumor immune evasion through T-cell dysfunction and T-cell exclusion. Furthermore, expression of EZH2 exhibited a strong correlation with several immunotherapy-associated responses (i.e., immune checkpoint molecules, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) status, and neoantigens), suggesting that EZH2 appeared to be a novel target for evaluating the therapeutic efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]