The tumor microenvironment (TME) is crucial to neoplastic processes, fostering proliferation, angiogenesis and metastasis. Epigenetic regulations, primarily including DNA and RNA methylation, histone modification and non-coding RNA, have been generally recognized as an essential feature of tumor malignancy, exceedingly contributing to the dysregulation of the core gene expression in neoplastic cells, bringing about the evasion of immunosurveillance by influencing the immune cells in TME. Recently, compelling evidence have highlighted that clinical therapeutic approaches based on epigenetic machinery modulate carcinogenesis through targeting TME components, including normalizing cells’ phenotype, suppressing cells’ neovascularization and repressing the immunosuppressive components in TME. Therefore, TME components have been nominated as a promising target for epigenetic drugs in clinical cancer management. This review focuses on the mechanisms of epigenetic modifications occurring to the pivotal TME components including the stroma, immune and myeloid cells in various tumors reported in the last five years, concludes the tight correlation between TME reprogramming and tumor progression and immunosuppression, summarizes the current advances in cancer clinical treatments and potential therapeutic targets with reference to epigenetic drugs. Finally, we summarize some of the restrictions in the field of cancer research at the moment, further discuss several interesting epigenetic gene targets with potential strategies to boost antitumor immunity.