Immunomodulatory Effects of Hypomethylating Agents in Myelodysplastic Syndromes: Mechanisms and Therapeutic Implications

Yi Liu; Jiayi  Zhao; Ting Wei; Guanlun Gao; Qingshan Li

doi:10.54097/fqtz8e02

Authors

Yi Liu
Jiayi Zhao
Ting Wei
Guanlun Gao
Qingshan Li

DOI:

https://doi.org/10.54097/fqtz8e02

Keywords:

Myelodysplastic Syndromes, Immune Modulation, Hypomethylating Agents

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and an increased risk of progression to acute myeloid leukemia. Increasing evidence indicates that immune dysregulation and chronic inflammatory signaling play critical roles in the pathogenesis and progression of MDS. Hypomethylating agents (HMAs), particularly azacitidine and decitabine, remain the backbone of treatment for patients with higher-risk disease. Beyond their canonical epigenetic effects, HMAs exert broad immunomodulatory activities that influence both innate and adaptive immunity. These agents can activate endogenous retroviral elements, induce viral mimicry, and enhance antigen presentation, thereby improving immune recognition of malignant cells. In addition, HMAs modulate the function of multiple immune cell populations, including natural killer cells, T lymphocytes, dendritic cells, macrophages, and myeloid-derived suppressor cells, ultimately reshaping the bone marrow immune microenvironment. However, clinical responses to HMAs remain heterogeneous, and treatment resistance frequently develops. A better understanding of the immunological basis of HMA activity may facilitate the development of more effective therapeutic strategies, particularly rational combination approaches with immunotherapy. This review summarizes current knowledge of immune dysregulation in MDS and discusses the immunomodulatory mechanisms and therapeutic implications of HMAs.

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