With the advances in cancer immunity regulation and immunotherapy, the effects of histone modifications on establishing antitumor immunological ability are constantly being uncovered. Developing combination therapies involving epigenetic drugs (epi-drugs) and immune checkpoint blockades or chimeric antigen receptor-T cell therapies are promising to improve the benefits of immunotherapy. Histone H3 lysine 4 trimethylation (H3K4me3) is a pivotal epigenetic modification in cancer immunity regulation, deeply involved in modulating tumor immunogenicity, reshaping tumor immune microenvironment, and regulating immune cell functions. However, how to integrate these theoretical foundations to create novel H3K4 trimethylation-based therapeutic strategies and optimize available therapies remains uncertain. In this review, we delineate the mechanisms by which H3K4me3 and its modifiers regulate antitumor immunity, and explore the therapeutic potential of the H3K4me3-related agents combined with immunotherapies. Understanding the role of H3K4me3 in cancer immunity will be instrumental in developing novel epigenetic therapies and advancing immunotherapy-based combination regimens.