The tumor microenvironment (TME) is a multifaceted and dynamic system that plays a crucial role in tumor initiation, progression, metastasis, and response to therapies [1]. In addition to stromal cells, fibroblasts, and endothelial cells, the TME comprises innate and adaptive immune cells that manipulate immune responses and guide tumor progression. Among the diverse innate immune cell types, myeloid-derived suppressor cells (MDSCs) have emerged as universal regulators of the antitumor immune response [2], [3]. As cancer progresses, TME-derived molecules accelerate the accumulation of MDSCs, which in turn promote tumor proliferation, angiogenesis, metastasis, and immune evasion [4]. Furthermore, MDSCs contribute to immunotherapy resistance and correspond with poor prognosis in cancer patients. Adequate clinical studies have defined MDSCs as predictive markers of cancer, and intensive efforts to explore therapies targeting MDSCs are ongoing [5], [6], [7]. Recently, studies have uncovered that MDSCs employ epigenetic mechanisms to bolster their immunosuppressive capabilities. Meanwhile, therapeutic interventions targeting epigenetic modifications in MDSCs have shown promising potential as effective antitumor strategies [8].

Epigenetic modifications represent the phenomenon of phenotype change in the absence of genotype alteration. Epigenetic modifications mainly consist of DNA modifications, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs), in which histone modifications are the most studied in MDSCs [9], [10], [11]. As a well-studied class of epigenetic modifications, histone modifications include acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADPribosylation, and deamination, which mainly occur in the N-terminal tail regions of histones and can alter chromatin compaction and accessibility, thereby regulating gene transcription and chromatin function [12], [13]. In addition to tails, several modification sites are present in the central globular domains of histones. Histone core modifications not only directly regulate gene transcription but also affect processes such as DNA repair, replication, stemness, and changes in cell state [14].

In this review, we will discuss the influence of TME on histone modifications in MDSCs and provide an overview of the role of histone modifications and modifiers in MDSCs. Additionally, we will highlight the epigenetic interventions that can change histone modifications in MDSCs and discuss open questions in the field and directions for future research.