Evidences highlight the role of various CD4⁺ helper T cells (CD4⁺ Th) subpopulations in orchestrating the immune responses against cancers. Epigenetics takes an important part in the regulation of CD4⁺ Th polarization and plasticity. In this review, we described the epigenetic factors that govern CD4⁺ T cells differentiation and recruitment in the tumor microenvironment and their subsequent involvement in the antitumor immunity. Finally, we discussed how to manipulate tumor reactive CD4⁺ Th responses by epigenetic drugs to improve anticancer immunotherapy.