Epigenetic regulation has been demonstrated as an important approach that controls gene activity without altering the DNA sequence itself. Epigenetic modification, which dictates how genes are turned on or off, has been widely found in all kinds of developmental and disease states and primarily includes DNA methylation, histone modification and non-coding RNA molecules (Fig. 1). (Al Aboud, Tupper, and Jialal, 2025; Cheng et al., 2019; Jaenisch and Bird, 2003) Based on the environmental factors, epigenetic regulation helps determine which genes are expressed in different cells and at different times, playing a crucial role in various cell functions, such as development, differentiation, adaptation and malfunction.

Emerging research highlights that the interaction between the immune system and the central nervous system (CNS) is largely regulated by epigenetic mechanisms. Epigenetic regulated gene expression patterns allow both the immune system and CNS to adapt to environmental cues and physiological stressors. For instance, repeated exposure to endotoxins can lead to a loss of permissive epigenetic marks, resulting in a tolerized response, while genotoxic stress can enhance these marks, leading to a primed state (Zhang et al., 2022). Additionally, immune-CNS communication is epigenetically tuned, maintaining CNS homeostasis and modulating neuroinflammation. This bidirectional relationship underscores the importance of epigenetic regulation in maintaining a steady state and offers insight into the pathogenesis of disorders such as stroke and CNS tumor.

The human immune system, including the innate and adaptive immune system, is a complex network of cells, tissues, and organs that work together to respond to stimuli in the environment. The ability of different immune cells to change their function in response to internal or external factors is crucial to immune homeostasis (Justiz Vaillant, Sabir, and Jan 2025). It has been well demonstrated that epigenetic regulation plays a vital role in immune cells differentiation and proliferation (Placek et al., 2019; Frias et al., 2021; Fiordoro et al., 2024). Furthermore, the activation and trafficking of immune cells to the disease, as well as their subsequent effector functions, are also dependent upon precise epigenetic regulation. On the other hand, aberrations of epigenetic modification are closely connected to the aberrant function of immune cells, and subsequent pathological conditions, such as immune dysfunction and cancer.

In this review, we discuss recent findings (mostly from 2014 to 2024) regarding epigenetic regulation of immune cell behavior in CNS physiology and pathology. First, we will compare how underlying epigenetic mechanisms regulate different immune cells behaviors in normal homeostatic conditions. Next, we will delineate how epigenetic regulation alters immune cell functions under different CNS disease models, including stroke, tumor, and inflammation. Lastly, we will discuss the implications of epigenetics mediated alterations in immune cells behaviors in the context of immunotherapy.