Table 1 Phenotypic and functional effects of epigenetic modifiers in key immune cell types

NK cells

DNMTs

DNA methyltransferase

DNA methylation

• Enhance IFN-γ expression

• Regulate KIR expression

Chan et al. [63] Luetke-Eversloh et al

[66]

Sohlberg et al. [69]

EZH2

Histone methyltransferase

H3K27me3

• Suppress IL-15R (CD122) and NKG2D expressions

Yin et al. [29]

Bugide et al. [30]

ASH1L

Histone methyltransferase

H3K36me3

• Positively regulate NK activation

Li et al. [62]

JARID2

Histone methyltransferase

H3K27me3

• Positively regulate NK activation

Li et al. [62]

KDM6B

Histone demethylase

H3K27me2/3

• Positively regulate NK activation

Li et al. [62]

UTY

Histone demethylase

H3K27me

• Positively regulate NK activation

Li et al. [62]

Macrophages

DNMTs

DNA methyltransferase

DNA methylation at promoters of Klf4, Socs1, Pparg

• Promote M1 polarization

Cheng et al. [75]

Yang et al. [76]

Niu et al. [2]

TET2

Methylcytosine dioxygenases

DNA methylation at promoters of immunosuppressive genes

• Promote M2 polarization

Pan et al. [77]

Lio et al. [23]

EHMT2

Histone methyltransferase

H3K9me3

• Suppress M1 polarization

Wang et al. [82]

ASH1L

Histone methyltransferase

H3K4me3

• Suppress IL-6 and TNFα production

Xia et al. [197]

SETD4

Histone methyltransferase

H3K4me1, H3K4me2

• Induce macrophage activation

• Increase IL-6 and TNFα expression

Zhong et al. [32]

SETD7

Histone methyltransferase

H3K4me1

• Promote M1 polarization,

• Increased S100A9 and S100A12 expressions

Mossel et al. [83]

SMYD2

Histone methyltransferase

H3K36me2

• Negative regulation of macrophage activation

Xu et al. [78]

SMYD3

Histone methyltransferase

H3K4me3

• Promote M1 polarization, Increased S100A9 and S100A12 expressions

Mossel et al. [83]

SMYD5

Histone methyltransferase

H4K20me3

• Negative regulation of macrophage activation

Stender et al. [79]

KDM6B

Histone demethylase

H3K27me

• Promote M2 polarization

Ishii et al. [80]

Satoh et al. [81] Yıldırım-Buharalıoğlu et al. [198] Xun et al. [34]

Raines et al. [35]

HDAC11

Histone deacetylase

AcH3

• Inhibit M2 polarization and activation

Hu et al. [199]

Shinohara et al. [38]

KAT2A/B

Histone acetyltransferase

H3K9ac

• Promote M2 activation

• Increase IL-6 expression

Hu et al. [199]

EP300

Histone acetyltransferase

Acetyl Histone H3

• Promote M2 activation

• Increase IL-6 expression

Wang et al. [84]

PRMT1

Arginine methyltransferase

Arginine methylation of c-Myc

• Promote M2 activation

Tikhanovich et al. [85]

CD8 + T cells

DNMT3A

DNA methyltransferase

DNA methylation

at promoters of Eomes, Tbx21 and Tcf7 and

promoters of naive-associated genes

• Promote tumor-specific T cell dysfunction

• Establish de novo DNA methylation program for T cell exhaustion

• Repress naive-associated genes in effector CD8+ T cells

Schietinger et al

[97]

Ghoneim et al. [96] Youngblood et al

[200]

TET2

Methylcytosine dioxygenases

DNA methylation

• Regulate CD8+ T cell memory differentiation

• Promote terminal exhaustion of T cells

Carty et al. [201] Jordan et al. [98]

EZH2

Histone methyltransferase

H3K27me3

• Promote SLEC and effector T cell differentiation

• Anti-tumor immunity

Karantanos et al. [53]

Schietinger et al. [97]

Zhao et al. [202]

Gray et al. [87]

EHMT2

Histone methyltransferase

H3K9me3

• Suppress the development of memory precursor CD8⁺ T cells

• Repress Il2ra and Cd27

Shin et al. [89]

BMI1

Epigenetic repressor, Component of the polycomb group complex 1 (PRC1)

Targets of PRC1 complexes

• Promote T cell activation and expansion

Heffner et al. [203] Henning et al. [4]

BRD4

Bromodomain-containing protein

Acetylated lysines

• Promote T cell differentiation into an effector memory phenotype

• Enhance T cell persistence and antitumor effects

Kagoya et al. [40]

HDAC2

Histone deacetylase

Acetylated histones

• Suppress the development of memory precursor CD8⁺ T cells

• Repress Il2ra and Cd27

Shin et al. [89]

KDM1A (LSD1)

Histone demethylase

H3K4me, H3K9me

• Promote terminal differentiation in exhausted CD8 + T cells

Liu et al. [33]

SIRT1

NAD⁺-dependent deacetylase

N/A

• Inhibit effector T cell differentiation

Kuroda et al. [204]

TOX

Transcription factor/Chromatin modifier

Binds DNA via the HMG-box motif

• Promote T cell persistence

• Drive CD8+ T cell exhaustion

Khan et al. [101]

Alfei et al. [103]

Scott et al. [102]

Yao et al. [205]

Seo et al. [206]

Wang et al. [207]

Treg

HDAC

Histone deacetylase

FOXP3

• Decreased binding of FOXP3 to chromatin

• Destabilize FOXP3+ Treg cells

Samanta et al. [39]

EZH2

Histone methyltransferase

H3K27me3

• Mediate immunosuppressive functions in tumor-infiltrating Tregs

Wang et al. [113] Goswami et al. [54]

Dendritic cells

TETs

Methylcytosine dioxygenases

DNA methylation

• Modulate dendritic cell activation

Li et al. [208]

EZH2

Histone methyltransferase

H3K27me

• Promote dendritic cell activation

Li et al. [124]

DOT1L

Histone methyltransferase

H3K79me2

• Inhibit maturation of BMDCs in cancer

Zhou et al. [31]

HDAC

Histone deacetylase

Acetylated histones

• Promote maturation of DCs from monocyte

Nencioni et al. [122]

SIRT6

NAD⁺-dependent deacetylase

H3K9ac

• Promote dendritic cell migration

Ferrara et al. [36]

MDSC

Class I HDACs

Class I histone deacetylases

Acetylated histones

• Promote immune suppressive activity of G-MDSC

Hashimoto et al. [36]

HDAC2

Class I histone deacetylase

Acetylated histones

• Promote phenotypic switch from M-MDSC to G-MDSC

Youn et al. [37]

HDAC6

Class IIb histone deacetylase

Acetylated histones

• Promote immune suppressive activity of M-MDSC

Hashimoto et al. [36]

HDAC11

Class VI histone deacetylase

Acetylated histones

• Negatively regulate MDSC expansion and function

Sahakian et al. [128]