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The development and progression of leukemia are driven not only by intrinsic genetic and epigenetic alterations in leukemia cells, but also by the dynamic remodeling of immune niches within the bone marrow microenvironment (BMM). Accumulating evidence has indicated that leukemic cells can reshape the immune microenvironment through cytokine secretion, metabolic reprogramming, and other mechanisms, inducing T-cell dysfunction/exhaustion, impaired NK-cell effector functions, and immunosuppressive polarization of myeloid cells, thereby establishing a protective niche that facilitates disease progression, drug resistance, and relapse. In parallel, epigenetic mechanisms such as DNA methylation, histone modification, and RNA modifications bridge the phenotypic plasticity of leukemic cells and immune evasion processes by regulating antigen presentation, interferon signaling pathways, chemokine profiles, and immune checkpoint expression, thereby influencing the response to immunotherapy. This review centers on the core conceptual framework of "immune microenvironment remodeling - epigenetic regulation - drug resistance and relapse - combination therapy strategies". It systematically outlines the key immunosuppressive networks and their epigenetic foundations across different leukemia subtypes. Emphasis is placed on the advances and challenges in combining epigenetic drugs, such as demethylating agents and histone deacetylase inhibitors, with immune checkpoint inhibitors, BCL-2 inhibitors, and microenvironment-targeted therapies. Furthermore, it outlines future directions in microenvironment subtyping and precision interventions driven by single-cell and spatial multi-omics technologies, aiming to provide a theoretical basis for optimizing combination treatment strategies in leukemia.