Histone modifications across cancers: mechanisms, therapy and clinical translation.

Introduction

Cancer is still one of the major health issues worldwide. In the year 2022, there were nearly 20 million new cases and 9.7 million deaths recorded globally [ 1 ]. Asia contributed half of the cases (49.2%), as well as most of the cancer deaths (56.1%), while Europe contributed a quarter of the cases [ 2 ]. The projections suggest that by the year 2050, new cases of cancer could reach up to 30.5 million annually, with mortality rates expected to increase by 74.5% compared to the estimates for the year 2024 [ 3 ]. The survival rates for cancer patients show significant variability depending on the type and geographical location. Although the relative survival rates for all cancers in the US have shown an improvement from 49% in the 1970s to 69% from 2014 to 2020, disparities still exist for some cancers. For example, pancreatic (13%), liver (22%), and lung cancers have poor survival rates, whereas thyroid (98%), prostate (97%), and testicular cancers (95%) have better survival rates. These disparities are even higher in low- and middle-income countries, where survival rates are significantly low owing to the lack of access to early detection and treatment modalities [ 4 ]. Even within the continent of Europe, Eastern European countries have lower survival rates than Western countries due to unequal access to healthcare facilities [ 5 ]. In Asia, Japan and South Korea have high survival rates for breast and prostate cancers, exceeding 86% and 89%, respectively; however, lung cancer survival remains dishearteningly low at 32.9% and 25.1%, respectively [ 6 , 7 ]. The current cancer treatment modalities such as surgery, radiation, chemotherapy, and immunotherapy face the same challenges as before. Genomic instability, epigenetic changes, and heterogeneity are all factors that can induce drug resistance, a major problem. Immunotherapy agents such as immune checkpoint inhibitors produce durable responses in only 15–30% of the total patient pool due to the lack of patient selection biomarkers and immunosuppressive microenvironment [ 8 ]. Tumor heterogeneity, both intratumoral and intertumoral, makes it difficult to develop effective treatment strategies, leading to resistance and recurrence. To address these issues, new strategies must be developed. One of these new strategies could be epigenetic therapy, specifically targeting histone modifications, which can overcome resistance and restore responses.

Histone modifications are chemical changes that happen to histone proteins after they have been translated. Histone proteins are important parts of nucleosomes, which are the basic repeating units of chromatin. These changes, which mainly happen on the N-terminal tails of histones (e.g., H3, H4), include acetylation, methylation, phosphorylation, ubiquitination, and others [ 9 ]. They are essential for chromatin dynamics and gene regulation because they modify how easily DNA can be accessed by transcriptional machinery. For example, histone acetylation usually neutralizes the positive charge of histones, which lowers the DNA-histone affinity and encourages a “open” chromatin state that is beneficial for transcription. On the other hand, some methylation marks, like H3K27me3, are linked to chromatin that is tightly packed and stops transcription. The fact that these changes can be combined, often called the “histone code”, means that they can act as a flexible signaling system that controls gene expression, DNA repair, and other chromatin-templated processes without changing the DNA sequence itself [ 10 ].

The malfunction of histone modifications is increasingly acknowledged as a characteristic of cancer pathogenesis, as it may result in the inappropriate activation of oncogenes or the repression of tumor suppressor genes. This dysregulation often arises from recurrent mutations, amplifications, or deletions in genes that encode histone-modifying enzymes, categorized as “writers” (e.g., methyltransferases), “erasers” (e.g., demethylases), and “readers” (e.g., bromodomain proteins). For instance, gain-of-function mutations or overexpression of EZH2 , the catalytic subunit of Polycomb Repressive Complex 2 (PRC2) that facilitates H3K27 trimethylation (H3K27me3), are present in lymphomas, breast cancer, and many more malignancies [ 11 ]. EZH2 hyperactivation stimulates the silencing of tumor suppressors, which allows cells to grow and spread without control. KDM6A (UTX), a histone demethylase that removes restrictive H3K27me3 marks that normally serves as a tumor suppressor, is often deactivated by mutations in malignancies including breast cancer, bladder cancer, and leukemia [ 12 ]. These modifications disturb conventional gene expression patterns, facilitating neoplastic transformation.

Recurrent mutations in histone modifiers are common in a variety of cancers, which shows how essential they are in the development of tumors. In lung cancer, histone acetylation (like the global loss of H4K16ac) and methylation (like the overexpression of EZH2 ) are frequently dysregulated, and these changes are often linked to harmful prognosis and resistance to treatment [ 13 , 14 ]. In breast cancer, abnormal histone methylation, like EZH2-mediated silencing of hormone receptors, causes tumors to be different from each other and spread to other parts of the body, especially in triple-negative subtypes [ 15 ]. Colorectal cancer also shows a lot of epigenetic changes, like mutations in histone methyltransferases (like SETD2 ) and demethylases, which help tumors grow through pathways like Wnt signaling [ 16 ]. The fact that these mutations happen a lot in several distinct kinds of cancer shows that disrupting chromatin homeostasis is a key way that cancer cells grow, which is why histone modifiers are an appealing target for treatment.

It is now well known that epigenetic dysregulation, especially alterations in histones, plays a key role in the development of tumors (Fig. 1 ). Moreover, comprehensive studies have elucidated how recurrent mutations in enzymes like EZH2 and KDM6A perturb the epigenetic landscape, resulting in dysregulated gene expression programs that drive cancer hallmarks [ 17 ]. Histone modifications are acknowledged as significant contributors to various cancers; however, their subtype-specific functions, therapeutic targeting difficulties, and complex interactions with genetic alterations and other cancer hallmarks are still inadequately investigated. For example, the functional importance of less-explored modifications such as histone phosphorylation (e.g., H3Y41ph) in signal transduction and ubiquitination (e.g., H2BK120ub) in transcriptional regulation across various cancer subtypes remains inadequately researched [ 18 , 19 ]. Moreover, the clinical application of epigenetic therapies is frequently obstructed by challenges related to drug resistance, selectivity, and an inadequate comprehension of the mechanisms by which tumor cells reorganize their epigenome in response to targeted therapies. This review aims to fill these gaps by looking at histone modifications in a broad way, comparing how they work and what they do across different types of cancer, from lung and breast cancer to colorectal tumors and blood cancers. We will examine how the tumor’s histone modification landscape affects the tumor-immune microenvironment, affecting how immune cells are recruited and how they respond to immunotherapies. Finally, some potential natural products with the function of affecting histone modifications will be discussed.

Fig. 1 Key milestones in cancer epigenetics research, emphasizing the transition from basic science to the current paradigm of integrative and therapeutic aspects

Histone modifications in cancer

Overview of histone modifications

Histone modifications are an important part of epigenetic regulation that controls how chromatin behaves and how genes are expressed without changing the DNA sequence itself. These covalent post-translational modifications (PTMs) primarily occur on the N-terminal tails of core histones (H2A, H2B, H3, H4) and encompass well-characterized marks such as acetylation and methylation, alongside less-explored modifications including phosphorylation, ubiquitination, and glycosylation. Specific enzymes called “writers” and “erasers” add and remove them dynamically, and “reader” proteins interpret them and bring in downstream effector complexes to change transcriptional states, DNA repair, replication, and the cell cycle [ 20 ]. In cancer, mutations, overexpression, or deletion of the modifying enzymes often throw off the exact balance of these changes, which leads to the activation of oncogenes or the silencing of tumor suppressor genes, which drives tumorigenesis and metastasis [ 21 ]. Although acetylation and methylation have been extensively studied in the field of oncology in the past decades, recent studies have emphasized the relevance of other modifications in the field of cancer research, such as phosphorylation, ubiquitination, glycosylation, sumoylation, ADP-ribosylation, lactylation, β-hydroxybutyrylation, crotonylation, and citrullination (Table 1 ).

Table 1 Summary of key histone modifications in cancer Modification Type Modified Residue Writer / Eraser / Reader Core Function in Cancer Acetylation Lysine (K), e.g., H3K9, H3K14, H3K27, H4K16 Writer: Histone acetyltransferases (HATs, e.g., p300/CBP, GCN5); Eraser: Histone deacetylases (HDACs, e.g., HDAC1-11); Reader: Bromodomain-containing proteins (e.g., BRD4) Loosens chromatin structure to promote oncogene activation; Abnormal acetylation (e.g., abnormal elevation of H4K16ac) is involved in the occurrence of lung cancer, breast cancer, and colorectal cancer, and HDAC inhibitors can reverse the abnormal phenotype. Methylation Lysine (K), Arginine (Arg, R); K can be mono-, di-, or tri-methylated (me1/me2/me3), e.g., H3K4me3, H3K9me3, H3K27me3, H3K36me3, H4K20me3 Writer: Histone methyltransferases (HMTs, e.g., EZH2, DOT1L, SUV39H1); Eraser: Histone demethylases (KDMs, e.g., KDM6A, KDM5B); Reader: Chromodomain- and Tudor domain-containing proteins (e.g., HP1, CDY) Function depends on modification site and methylation degree: H3K4me3 (oncogene activation), H3K27me3 (tumor suppressor gene silencing); Abnormal elevation of EZH2 drives lymphoma and prostate cancer; DOT1L-mediated H3K79me2 is involved in leukemia development. Phosphorylation Serine (S), Threonine (T), Tyrosine (Y), e.g., H3S10, H3S28, H2AXS139 (γ-H2AX) Writer: Serine/threonine kinases (e.g., Aurora A/B, ATM); Eraser: Phosphatases (e.g., PP1, PP2A); Reader: 14-3-3 and BRCT domain-containing proteins Involved in the regulation of cancer cell mitosis and DNA damage repair; Abnormal accumulation of γ-H2AX is associated with cancer genomic instability; Elevated H3S10ph promotes the proliferation of breast cancer and lung cancer cells. Ubiquitination Lysine (K), e.g., H2AK119ub, H2BK120ub Writer: Ubiquitin ligases (e.g., Ring1B, RNF2); Eraser: Deubiquitinases (e.g., USP22, BAP1); Reader: UIM and UBA domain-containing proteins Regulates oncogene transcription and DNA repair; Abnormal H2AK119ub silences tumor suppressor genes (e.g., p53); BAP1 mutation leads to abnormal deubiquitination, involved in the occurrence of kidney cancer and mesothelioma. Glycosylation Serine (S), Threonine (T), Asparagine (N); Mainly O-linked (O-GlcNAcylation) and N-linked glycosylation, e.g., H3S10GlcNAc, H4S47GlcNAc Writer: O-GlcNAc transferase (OGT); Eraser: O-GlcNAcase (OGA); Reader: Proteins containing O-GlcNAc-binding domains (e.g., WDR5) Involved in metabolic-epigenetic crosstalk, regulating chromatin structure and gene transcription; Abnormal O-GlcNAcylation is associated with cancer metabolic reprogramming, promoting proliferation and metastasis of breast cancer, liver cancer and gastric cancer; It can interact with other modifications (e.g., acetylation, phosphorylation) to regulate cancer progression. Sumoylation Lysine (K) Writer: SUMO ligases (e.g., PIAS family); Eraser: DeSUMOylases (e.g., SENPs); Reader: SIM domain-containing proteins Inhibits gene transcription and antagonizes acetylation/ubiquitination; Abnormal sumoylation can stabilize oncoproteins (e.g., c-Myc) and promote the progression of liver cancer and gastric cancer. ADP-ribosylation Glutamic acid (E), Arginine (R) Writer: PARP family (e.g., PARP1); Eraser: PARG, ARH3; Reader: PBZ and BRCT domain-containing proteins Involved in cancer cell DNA damage repair; PARP inhibitors can target and kill BRCA-mutated breast cancer and ovarian cancer; Abnormal ADP-ribosylation enhances cancer cell drug resistance. Lactylation Lysine (K), e.g., H3K18la, H3K9la Writer: p300 (with both acetyltransferase and lactyltransferase activity); Eraser: HDACs (some subtypes can mediate delactylation); Reader: To be clarified (presumed to be recognized by bromodomain-containing proteins) Links the Warburg effect to epigenetic regulation; Elevated H3K18la promotes colorectal cancer metastasis and pancreatic cancer immune escape; Targeting lactylation can enhance cancer treatment sensitivity. β-hydroxybutyrylation Lysine (K), e.g., H3K9bhb Writer: p300/CBP; Eraser: HDACs; Reader: Bromodomain-containing proteins Involved in metabolic-epigenetic crosstalk (related to ketolysis pathway); Abnormal modification is associated with metabolic reprogramming of liver cancer and pancreatic cancer, regulating cancer cell energy metabolism. Crotonylation Lysine (K), e.g., H3K4cr, H3K9cr Writer: p300/CBP, MOF; Eraser: HDACs (e.g., HDAC3, SIRT1); Reader: Bromodomain-containing proteins (e.g., BRD4) Associated with active enhancers to activate oncogene transcription; Abnormal elevation of H3K9cr is involved in leukemia and breast cancer occurrence, and can be used as a potential therapeutic target. Citrullination Arginine (R) → Citrulline (Cit), e.g., H3R2Cit, H4R3Cit Writer: Peptidylarginine deiminases (PADs, e.g., PAD4); Eraser: No clear specific eraser identified yet; Reader: To be further studied Regulates chromatin structure and immune response; PAD4-mediated histone citrullination promotes lung cancer and ovarian cancer metastasis, enhancing cancer cell immune escape ability.

Histone phosphorylation, as demonstrated by H3S10ph, serves a dual function in transcriptional activation and chromosome condensation during mitosis [ 22 ]. H3S10ph is often upregulated in cancer and is linked to a worse prognosis in cancers like breast cancer and glioblastoma. It plays a role in keeping the genome stable by marking DNA-RNA hybrids (R-loops). If these are not working properly, they can cause DNA damage and chromosomal instability, which is an indication of cancer. Aurora B, MSK1/2, and PIM1 are some of the kinases that add this mark. These kinases are frequently dysregulated in tumors. A significant mechanism is the “phospho-methyl switch,” in which H3S10ph stops repressive proteins like HP1 from binding to nearby H3K9me2/3. This stops heterochromatin from spreading and can even turn on oncogenes [ 23 ].

Histone ubiquitination, especially the mono-ubiquitination of H2BK120 (H2BK120ub), is another important change that plays a complicated role in cancer. H2BK120ub, mainly caused by the RNF20/40 E3 ligase complex, is usually linked to transcriptional activation and can act as a tumor suppressor [ 24 ]. For example, in triple-negative breast cancer, UBR7 promotes H2BK120ub, which stops tumors from growing and spreading. H2BK120ub helps bring repair elements to double-strand breaks in the DNA damage response. On the other hand, the deubiquitinase USP22, which is part of the SAGA complex, removes H2BK120ub [ 25 ]. Blocking USP22 increases H2BK120ub levels and makes it harder for γH2AX to form, which is a hallmark of DNA damage. This makes DNA repair harder and makes cancer cells more unstable [ 26 ].

Histone glycosylation, particularly O-GlcNAcylation, has been identified as a nutrient-responsive post-translational modification that connects cellular metabolism with epigenetic regulation. O-GlcNAcylation is the process by which O-GlcNAc transferase (OGT) adds O-linked N-acetylglucosamine (O-GlcNAc) to serine or threonine residues on histones. O-GlcNAcase (OGA) then processes it away [ 27 ]. The shift is often higher in cancers like breast, prostate, and colon cancer, and it helps tumors grow by controlling important processes. For instance, O-GlcNAcylation of H2B at serine 112 (H2BS112GlcNAc) makes it easier for a single ubiquitin molecule to be added to lysine 120 (K120) on H2B, which helps gene transcription [ 28 ]. O-GlcNAcylation can compete with phosphorylation at the same residue, as seen at H3S10, where higher levels of O-GlcNAcylation are linked to lower levels of phosphorylation, which affects how chromatin condenses during mitosis [ 29 ]. O-GlcNAcylation acts as a sensor for the hexosamine biosynthetic pathway, linking the availability of nutrients such as glucose, glutamine, and ATP to chromatin dynamics. This represents a mechanistic connection between metabolic reprogramming and epigenetic changes in cancer [ 30 ].

In histone sumoylation, small ubiquitin-like modifier (SUMO) proteins are covalently attached to lysine residues on histones H4, H2A, H2B, and H3. Unlike ubiquitination, in which the target protein is often marked for degradation, protein-protein interactions and subcellular localization are the major targets of sumoylation. With respect to chromatin, histone sumoylation is generally associated with transcriptional repression. It does so by facilitating the recruitment of repressive complexes such as histone deacetylases (HDACs) and heterochromatin protein 1 (HP1) or by counteracting activation marks [ 31 , 32 ]. This process is regulated by a series of enzymes including E1, E2 (Ubc9), and E3 enzymes such as the PIAS family. The reverse reaction is mediated by sentrin-specific proteases, also known as SENPs. The role of histone sumoylation in cancer development is complex and dependent on the context. For example, the sumoylation of histone H4 occurs at multiple lysine residues, including K5, K8, K12, K16, and K20, which has been implicated as a key factor in the maintenance of heterochromatin stability, and its deregulation has been implicated in genomic instability, a hallmark of cancer development [ 33 ]. Additionally, the overexpression of the sumoylation machinery has been implicated in cancer development. For instance, Ubc9 is overexpressed in a number of cancers and is associated with poor prognosis, thus offering a new avenue for the development of cancer therapy [ 34 ].

ADP-ribosylation is a distinctive and dynamic post-translational modification wherein ADP-ribose moieties are transferred from NAD+ onto protein targets. This can happen as mono(ADP-ribosylation) (MARylation) or poly(ADP-ribosylation) (PARylation). On histones, especially H2B and H3, this post-translational modification is mainly mediated by members of the PARP protein family, including PARP1, which ADP-ribosylates specific residues such as H2BK30, H3K27, and H3K37 [ 35 ]. The incorporation of these bulky, negatively charged ADP-ribose polymers is known to profoundly alter chromatin architecture, leading to an open, relaxed structure that is favorable for DNA repair, replication, and transcription [ 36 ]. This modification is undone by erasers such as PARG. The significance of ADP-ribosylation in cancer is substantial, especially given the central role of PARP1 in DNA damage response pathways. Histone PARylation is among the first responders to DNA damage, given its role in marking sites of DNA breaks for repair [ 37 ]. This is particularly relevant in cancers that have deficiencies in homologous recombination repair, such as BRCA1/2, for which PARP inhibitors (PARPi) have emerged as therapeutic agents that trigger synthetic lethality [ 38 ]. In addition to DNA damage response, aberrant PARPs have also been implicated in inflammation and transcription of oncogenes, thus securing their place as key players in cancer that is critical for therapeutic intervention.

Histone lactylation, a newly discovered epigenetic modification, was derived from the metabolic byproduct lactate, thus creating a direct link between the metabolic state, as determined by the Warburg effect or aerobic glycolysis, and gene expression. Lactylation was first discovered on lysine residues of histones, including H4K5la, H4K8la, and H3K18la, and is catalyzed by writers such as p300 [ 39 ]. Lactylation, like acetylation, was shown to activate genes, but, in contrast to acetylation, which is derived from the metabolic byproduct acetyl-CoA, lactylation was directly linked to the cellular metabolic state and specifically to high rates of lactate production. Lactylation was shown to play a critical role in modulating M1/M2 macrophages polarization. In later stages of the inflammatory response, continuous glycolytic pathway activation results in intracellular lactate accumulation, thereby promoting histone lactylation, especially of H3K18 at the promoters of genes involved in wound healing and immunosuppression, such as Arg1, Vegf, Il10, Tgfb1, and Mrc1/CD206 [ 40 ]. Within the tumor microenvironment (TME), the lactate-mediated histone lactylation process is hijacked by tumor-associated macrophages to promote the establishment of a pro-oncogenic M2-like phenotype, resulting in immune evasion, angiogenesis, and metastasis. Furthermore, in cancer, elevated lactate, which is a result of the Warburg effect, has been implicated in the regulation of histone lactylation, which may, in turn, lead to the expression of genes that regulate cell proliferation and angiogenesis [ 41 ]. For example, histone lactylation has been implicated in the regulation of tumor growth and immune surveillance in ocular melanoma and non-small cell lung cancer through the polarization of tumor-associated macrophages [ 42 , 43 ].

β-hydroxybutyrylation (Kbhb) is a histone modification that is derived from the ketone body β-hydroxybutyrate (BHB), which is produced in large quantities during metabolic stress conditions such as caloric restriction and fasting. This histone modification has been found on histones such as H3K9bhb and H3K14bhb and has been linked to an open chromatin configuration and transcription, which counteracts the repressive effects of histone deacetylases [ 44 ]. The larger and hydrophobic nature of the β-hydroxybutyryl group, compared to the acetyl group, is believed to better repel the histones from the DNA, allowing for the transcription factor to have greater access. In the context of cancer, the function of Kbhb is an emerging field of study. Although BHB has been shown to have anti-tumor effects, this is generally through the function of providing a metabolic fuel and/or signal. However, the direct function of providing an epigenetic mark suggests a more complex function. For example, in clear cell renal cell carcinoma, which is known for having significant metabolic reprogramming, decreased levels of Kbhb at the promoters of tumor suppressor genes have been observed implying that Kbhb may function as a tumor-suppressive mark in this context. In this way, lowering its expression would help silence these genes and increase lipolysis leading to tumor development [ 45 ].

Histone crotonylation, abbreviated as Kcr, is a short-chain lysine acylation mark that is both structurally and functionally distinct from acetylation. Kcr is derived from crotonyl-CoA, an intermediate of fatty acid oxidation and amino acid degradation. Histone crotonylation, such as H3K18cr and H4K8cr, is found at active gene promoters and enhancers and is enriched on genes that are involved in crucial cellular processes including cell cycle regulation, metabolic reprogramming, and signal transduction pathways [ 46 ]. Although the writers and erasers of both acetylation and crotonylation are the same, such as p300/CBP and HDACs, SIRT1-3, respectively, crotonylation has been found to be more potent at activating genes compared to acetylation because of its bulkier and more hydrophobic size, thus facilitating greater decompaction of chromatin [ 47 , 48 ]. Moreover, the alteration of histone crotonylation has been implicated in the pathogenesis of cancer. For example, the reduction of global levels of histone crotonylation has been observed in hepatocellular carcinoma and other cancers, which correlates with poor clinical outcome and metastasis [ 49 , 50 ]. Such reduction could lead to the repression of tumor suppressor genes, implying that the proper regulation of histone crotonylation is crucial for the suppression of tumorigenic phenotypes. The crosstalk between acetylation and crotonylation at the same lysine residue introduces another dimension to the “histone code” in cancer.

Citrullination is a special post-translational modification, where the amino acid arginine, which is one of the most common residues found on histone tails, is converted into citrulline. This is not an addition of a chemical group, but rather a deimination reaction, and it is carried out by the peptidylarginine deiminase family of enzymes, most specifically PAD4 [ 51 ]. By converting the positively charged amino acid into a neutral amino acid, this modification has the effect of dramatically altering the positive charge of the histones, and hence the interaction between the histones and the negatively charged DNA backbone. This has the effect of directly leading to the decondensation of the chromosomes, and it also antagonizes the modification of arginine methylation, which is found at active genes, by removing the target for the methyltransferases. This is an important modification for processes such as neutrophil extracellular trap formation, NETosis, but it has profound effects if it is dysregulated, such as in the case of cancer [ 52 ]. PAD4 overexpression has been observed in various cancers, including breast, lung, and colon cancers. Overexpression of PAD4 results in the inhibition of histone arginine methylation and the decompaction of chromatin structures at promoters of genes involved in the processes of cell proliferation and invasion, resulting in the activation of the transcription of these genes [ 53 ]. Moreover, citrullination of histone H3 at arginine 8 (H3R8Cit) and histone H4 at arginine 3 (H4R3Cit) blocks the methylation of the sites in these histones, which has been associated with the epigenetic inactivation of the tumor suppressors, including p21. In the TME, this mechanism might result in the tumor-promoting and metastasis-promoting activities of NETs. It has been reported that citrullination of histones in NETs induces the proliferation and migration of cancer cells, increasing their resistance to the host’s immune system [ 54 , 55 ].

In the following sections, this review aims to discuss the implications of these findings with respect to cancer. Due to the nascent nature of this field of study, as well as the limited number of potential drug candidates, this review will specifically discuss two of the more well-characterized processes, namely methylation and acetylation.

Functional implications in cancer

Histone modifications are not just epigenetic spectators; they actively drive tumorigenesis by disrupting fundamental cancer hallmarks, leading to significant functional consequences. These changes have a direct effect on how important oncogenes and tumor suppressor genes are expressed, which in turn shifts important cellular processes. For example, PRC2 and its catalytic subunit EZH2 put down repressive marks like H3K27me3, which are often found at the promoters of tumor suppressor genes like p16 INK4a and RB . This stops the genes from functioning and lets the cell cycle go on without control [ 56 ]. On the other hand, triggering motifs like H3K4me3 and histone acetylation (e.g., H3K27ac) frequently occur at the enhancers and promoters of strong oncogenes like MYC and KRAS , which makes their pro-tumorigenic signals more powerful [ 57 , 58 ]. The mutant histone H3K27M, which is found in some pediatric gliomas, works as a dominant-negative inhibitor of PRC2. This causes an overall decrease in H3K27me3, but it also causes gene-specific hypermethylation and activation of oncogenic pathways [ 59 ]. Moreover, histone modification enzymes can directly engage with transcription factors to refine gene expression programs critical for cancer advancement. Figure 2 shows this complicated regulatory network, which connects certain histone modifications to processes that lead to tumors.

Fig. 2 Mechanistic Model Linking Histone Modifications to Tumorigenic Processes. A Core transcriptional regulation of oncogenes and tumor suppressor genes. The above schematic shows a general overview of the role of histones in the regulation of gene expression in cancer. Activating complexes, such as HAT and MLL, are shown to deposit histone marks such as H3K4me3 and H3K27ac, respectively, on the promoters/enhancers of oncogenes like MYC and KRAS, leading to their activation and subsequent overexpression in tumors. On the other hand, PRC2, through its catalytic subunit EZH2, deposits the repressive histone mark H3K27me3 on the promoters of tumor suppressor genes like RB1 and TP53, leading to their silencing and uncontrolled cell cycle progression in tumors. The histone mutation H3K27M is shown to reduce global H3K27me3 levels while paradoxically leading to hypermethylation and activation of specific genes. B The metabolic-epigenetic axis. This panel emphasizes the connection between cancer cell metabolism and the epigenetic landscape. The increase in glycolytic flux and lipid metabolism increases the nuclear pool of acetyl-CoA, which is crucial for the activity of HATs. The activity of enzymes such as ACLY is required for this process and is associated with the histone acetylation of genes such as H3K27ac, which is associated with the transcription of genes required for cell growth and proliferation. C Convergence on downstream tumorigenic processes. The aberrant gene expression profiles in ( A ) and ( B ) ultimately converge on several tumorigenic processes. These processes include the EMT, immune evasion through mechanisms such as PD-L1 modulation and T-cell suppression, and metabolic reprogramming to aerobic glycolysis and lipid metabolism. Abbreviations: HAT, histone acetyltransferase; MLL, mixed lineage leukemia; PRC2, Polycomb Repressive Complex 2; EZH2, enhancer of zeste homolog 2; ACLY, ATP-citrate lyase; EMT, epithelial-mesenchymal transition; PD-L1, programmed death-ligand 1

The interaction between cellular metabolism and histone modifications, especially acetylation, constitutes a critical axis of epigenetic interaction in cancer. The accessibility of acetyl-CoA, a necessary co-factor for HATs, is closely related to the cell’s metabolic state. A lot of cancer cells change to aerobic glycolysis and make more lipids, both of which can raise the amount of acetyl-CoA in the nucleus [ 60 ]. For instance, ATP-citrate lyase (ACLY) changes citrate that comes from glucose into acetyl-CoA in the nucleus. This directly connects the flow of glycolysis to the acetylation of histones. This higher level of acetyl-CoA can cause histones to become hyperacetylated at the promoters and enhancers of genes that help cells grow and divide [ 61 ]. Conversely, in nutrient-deprived environments or via pharmacological blockade with specific metabolic pathways, diminished acetyl-CoA concentrations can result in widespread histone hypoacetylation and the repression of tumorigenic transcripts. This metabolic-epigenetic axis is apparent in multiple cancer types; in hepatocellular carcinoma, increased acetyl-CoA production from various fuel sources facilitates histone acetylation and tumor proliferation, whereas in breast cancer, oncogenic signaling may augment acetyl-CoA production to maintain an oncogenic transcriptome [ 62 ].

Based on this mechanistic understanding, several strategies targeting metabolism have been used therapeutically. Ketogenic diet-based metabolic approaches that induce an elevation in the plasma concentration of BHB were found to enhance the histone Kbhb at the promoters of tumor-suppressive genes such as TP53 and FOXO3a, thus increasing the transcription of these genes and inhibiting the progression of colorectal cancer xenografts [ 63 ]. Calorie restriction and fasting, which limit the systemic concentrations of glucose and insulin, cause depletion of nuclear acetyl-CoA, resulting in inhibition of histone acetylation and consequent decreased tumor growth in breast cancer and glioblastoma models [ 64 , 65 ]. Pharmacologically, inhibitors of ACLY, including BMS-303,141 and bempedoic acid, decrease glucose-dependent acetyl-CoA synthesis, leading to decreased levels of histone H3K27ac and H3K9ac at oncogenic genes, causing cell proliferation inhibition in prostatic cancer models [ 66 , 67 ]. Likewise, inhibitors of glutaminase such as CB-839 (telaglenastat) inhibit glutamine-derived α-ketoglutarate, which is essential for the activity of ten-eleven translocation family DNA demethylases and Jumonji C domain histone demethylases, resulting in locus-specific methylation of H3K4me3 and H3K27me3, affecting gene expression pathways and inhibiting the growth of triple-negative breast cancer [ 68 , 69 ]. These examples illustrate the therapeutic potential of targeting the metabolic-epigenetic axis in cancer.

Histone modifications and the tumor immune microenvironment

Histone modifications have recently been identified as important factors that contribute to the immunogenic nature of cancer cells as well as the tumor immune microenvironment (TIME). The repressive histone modification H3K27me3, catalyzed by EZH2 in its role as the catalytic unit of PRC2, directly inhibits the transcription of T-helper 1 (Th1)-type chemokines CXCL9 and CXCL10, which play a key role in attracting effector CD8 + T cells into tumors [ 70 ]. Moreover, the recruitment of EZH2 to the promoter regions of genes coding MHC-I antigens and TAP1/2 facilitates the repression of antigen presentation in tumor cells, thus facilitating their immune escape [ 71 ]. This epigenetically based silencing mechanism causes the TME to be “cold,” with minimal T cell penetration and immunogenicity. Thus, the pharmacologic inhibition of EZH2 through tazemetostat promotes reexpression of these chemokines and restoration of MHC-I presentation at the surface of cells, resulting in greater CD8 + T cell infiltration and response to immune checkpoint blockade therapy in experimental models of ovarian, small cell lung, and melanoma cancers [ 72 ].

However, the H3K4me3 tag, which is installed by COMPASS-related histone methyltransferases such as the MLL complex, is found at the promoters of several other genes in various cancers, including the immune checkpoint ligand PD-L1 (CD274) and the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 [ 73 ]. This modification leads to elevated expression levels of immunosuppressive ligands and hence T cell exhaustion and immune escape. The inhibition of the MLL protein complex by inhibitors like MI-463 and MI-503 leads to a reduction of H3K4me3 marks in the PD-L1 promoter region and thus transcriptional downregulation of PD-L1, and inhibition of LSD1 by inhibitors such as bomedemstat leads to reduced PD-L1 expression levels [ 74 ]. In addition to that, the repressive mark of H3K9me3, placed by SETDB1 and read by HP1, acts to transcriptionally silence retroviruses. The pharmacologic or genetic suppression of SETDB1 results in viral mimicry, which is defined as an induction of double-stranded RNA, activation of the Type I interferon pathway via the MDA5/MAVS axis, and the establishment of anti-tumor immunity [ 75 , 76 ].

Key proteins and signaling pathways

In addition to the inherent mutational landscape of epigenetic enzymes, canonical oncogenic drivers continually restructure the epigenetic landscape to promote neoplastic programs. An example of this is mutant KRAS , which causes major changes in transcription by bringing in and changing histone modifiers. In pancreatic ductal adenocarcinoma and colorectal cancer, oncogenic KRAS signaling has been demonstrated to enhance the expression of the histone methyltransferase EZH2 . The MAPK pathway leads to this, which raises global H3K27me3 levels and turns off important tumor-suppressive and differentiation pathways [ 77 ]. Moreover, mutant KRAS participates in a positive feedback loop with the epigenome. It can help histone demethylases like KDM5A work better, which keeps cells in a dedifferentiated, therapy-resistant state [ 78 ]. Importantly, KRAS -driven tumors frequently demonstrate increased histone acetylation at the promoters and enhancers of pro-proliferative genes. This is made easier by the fact that acetyl-CoA, an important metabolite and substrate for HATs, is facilitated more, which connects the KRAS -driven metabolic reprogramming directly to the epigenetic state [ 79 ]. The reliance of mutant KRAS tumors on particular epigenetic regulators, including EZH2 and BRD4, indicates essential co-dependency and presents a logical therapeutic strategy for targeting these otherwise “undruggable” oncogenes via their epigenetic co-factors [ 80 ]. The functions of histone-modifying enzymes are often contingent on specific contexts, exhibiting considerable variation across different cancer types and molecular subtypes, thereby highlighting the intricacy of the cancer epigenome. Table 2 provides a systematic summary of the functional activities of these and other important histone-modifying enzymes, emphasizing their context-dependent actions across the main tumor subtypes.

Table 2 Key histone-modifying enzymes and their roles in cancer Enzyme / Complex Gene(s) Function Role in Cancer Associated Tumor Subtypes Reference PRC2 / EZH2 EZH2 , SUZ12 , EED Writer: Catalyzes H3K27me3, a repressive mark. Oncogenic: Frequently overexpressed. Silences tumor suppressors (e.g., CDKN2A). Gain-of-function mutations in lymphoma. Breast (Basal-like/TNBC), Prostate Cancer, B-cell Lymphomas, Glioblastoma [ 81 ] SETD2 SETD2 Writer: Catalyzes H3K36me3, linked to transcriptional elongation and DNA repair. Tumor Suppressive: Commonly inactivated by mutations or deletions, leading to genomic instability. Clear Cell Renal Cell Carcinoma, Lung Adenocarcinoma, Glioblastoma [ 82 ] Histone Deacetylases (HDACs) HDAC1 , HDAC2 , HDAC3 (Class I); HDAC4-7 (Class IIa) Erasers: Remove histone acetyl marks, promoting chromatin condensation. Oncogenic: Overexpressed, leading to repression of differentiation and tumor suppressor genes. Pan-cancer (e.g., Colorectal, Lung Adenocarcinoma, T-cell Lymphomas) [ 83 ] KDM5 Family KDM5A , KDM5B Erasers: Demethylate H3K4me2/3, a mark of active transcription. Oncogenic: Overexpressed, promotes drug tolerance and a stem-like state by silencing differentiation genes. Breast Cancer, Lung Adenocarcinoma, Melanoma [ 84 ] KDM6A/B KDM6A/B Eraser: Demethylates H3K27me3, leading to gene activation. Tumor Suppressive: Frequently inactivated by mutations, preventing activation of differentiation programs. Bladder Cancer, Leukemia, Breast Cancer [ 85 , 86 ] BRD4 BRD4 Reader: Binds acetylated histones (e.g., H3K27ac), recruits transcriptional machinery like P-TEFb. Oncogenic: Amplified or overexpressed, drives super-enhancer-mediated expression of oncogenes like MYC. Acute Myeloid Leukemia, Breast Cancer, Gastric Cancer [ 87 ]

Interplay with other epigenetic layers

Histone modifications do not work alone; they are part of a complicated, interconnected epigenetic network. They work with other regulatory mechanisms, like DNA methylation and non-coding RNAs, to keep oncogenic gene expression states stable. A quintessential illustration of this synergy is the collaborative repression of the tumor suppressor gene CDKN2A ( p16 INK4a ). In many types of cancer, such as glioblastoma and lung cancer, this locus often shows both promoter DNA hypermethylation and repressive histone methylation (H3K27me3 and H3K9me2/3) at the same time [ 88 ]. The interaction is two-way: DNA methylation can help bring in proteins that promote a repressive histone state, and on the other hand, some repressive histone marks can direct DNA methyltransferases (DNMTs) to specific genomic sites [ 89 ]. This sets off a cycle of epigenetic silencing that is stronger and less likely to be undone than either change on its own. Also, the MBD family of proteins, which bind to methylated DNA, often bring in complexes that contain histone deacetylases (HDACs), which causes local histone deacetylation and more chromatin compaction [ 90 , 91 ]. This combined axis of DNA methylation and histone deacetylation is a strong way to keep important cancer-related genes from being expressed for a long time.

In addition to DNA methylation, histone modifications extensively interact with non-coding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs) can function as modular scaffolds that physically attract and direct histone-modifying complexes to particular genomic loci. The most well-studied interaction is between the lncRNA XIST, which is necessary for X-chromosome inactivation, and the PRC2. XIST binds to PRC2 and informs it where to put H3K27me3 on the inactive X chromosome. For example, the lncRNA HOTAIR, which is overexpressed in breast, liver, and gastrointestinal cancers, serves as a link between PRC2 (which catalyzes H3K27me3) and the LSD1/CoREST/REST complex (which demethylates H3K4me). This creates a double repressive marker on genes that stop metastasis [ 92 ]. lncRNA ANRIL, which comes from the CDKN2A/B locus, also directly attracts PRC2 to silence this locus. This creates an autoregulatory feedback loop that encourages cell growth [ 93 ].

Therapeutic targeting and emerging strategies

Epigenetic drugs in cancer

The reversible character of epigenetic modifications has rendered them appealing therapeutic targets, resulting in the creation of epigenetic drugs (epi-drugs) aimed at restoring regular gene expression patterns in cancer cells [ 94 ]. The U.S. Food and Drug Administration approved various epi-drugs, mostly for blood cancers. These include DNA methyltransferase inhibitors (DNMTi) like azacitidine and decitabine for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and histone deacetylase inhibitors (HDACi) like vorinostat and romidepsin for cutaneous T-cell lymphoma. More recently, methyltransferase inhibitor (HMTi) tazemetostat, which inhibits EZH2, has been approved for follicular lymphoma and epithelioid sarcoma [ 95 ]. These agents operate via different mechanisms: DNMT inhibitors integrate into DNA and covalently sequester DNMT enzymes, resulting in DNA demethylation and the reactivation of silenced tumor suppressor genes, whereas HDAC inhibitors impede the removal of acetyl groups, fostering a more accessible chromatin state and the transcription of genes associated with differentiation and apoptosis [ 96 ]. Even though they have worked well in the clinic, there are still limitations, such as toxicity (especially with the nucleoside analogue DNMTi), limited effectiveness as monotherapies in solid tumors, and an increase of drug resistance [ 97 ]. The continual improvement of next-generation epi-drugs, such as non-nucleoside DNMTi and lysine acetyltransferase inhibitors (KATi), aims to address these limitations and enhance the repertoire of epigenetic therapeutics. The current landscape of these agents, from established drugs to novel compounds in development, is detailed in Table 3 .

Table 3 Epigenetic drugs in cancer: preclinical and clinical status Drug Class Examples Mechanism of Action Trial Phase / Approval Status Reported Efficacy Key Challenges Reference DNMT Inhibitors (DNMTi) Azacitidine, Decitabine Nucleoside analogues; incorporate into DNA, covalently bind and deplete DNMT1, leading to DNA demethylation and gene re-expression FDA Approved for MDS, AML, CMML, JMML Improved overall survival in MDS and AML; hypomethylating activity Toxicity (myelosuppression); chemical instability; limited efficacy in solid tumors [ 98 ] HDAC Inhibitors (HDACi) Vorinostat, Romidepsin, Panobinostat Block histone deacetylase activity, increase histone acetylation, leading to open chromatin and altered gene transcription. FDA Approved for CTCL, PTCL, Multiple Myeloma Objective responses in T-cell lymphomas; combination therapy in multiple myeloma Limited single-agent activity in many cancers; toxicities (thrombocytopenia, fatigue, GI disturbances) [ 99 , 100 ] EZH2 Inhibitors (HMTi) Tazemetostat Inhibits histone methyltransferase EZH2, reducing global H3K27me3 levels and reactivating silenced tumor suppressors FDA Approved for epithelioid sarcoma, follicular lymphoma Objective responses in ~ 60% of follicular lymphoma patients; durable clinical benefit Acquired resistance mechanisms; context-dependent oncogenic role of EZH2 [ 101 ] BET Inhibitors (BETi) JQ1, I-BET, OTX-015, Pelabresib (CPI-0610) Competitively bind to bromodomains of BET proteins (BRD2/3/4/BRDT), displacing them from acetylated chromatin and disrupting oncogenic transcription Phase I/II (e.g., Pelabresib in myelofibrosis); None FDA-approved for oncology as of early 2025 Reduced spleen volume and symptom burden in myelofibrosis (combined with ruxolitinib); downregulation of MYC in hematologic malignancies Dose-limiting toxicities (thrombocytopenia, GI effects); limited single-agent efficacy; conflicting results in solid tumors Phase 1: NCT02259114 , NCT03068351 [ 102 ], LSD1 (KDM1A) Inhibitors Bomedemstat (MK-3543) Inhibit lysine-specific demethylase 1, preventing demethylation of H3K4 and H3K9, which can affect differentiation and immune evasion Preclinical / Early Phase Trials Preclinical efficacy in AML models; potential to overcome immune evasion in melanoma and gastric cancer Specificity and toxicity concerns; clinical efficacy under evaluation Phase III: NCT06079879 KAT (HAT) Inhibitors TH1834 (Tip60 inhibitor) Inhibit lysine acetyltransferases, modulating histone acetylation and gene expression; Tip60 is involved in DNA damage response and metastasis Preclinical Significant in vivo activity against breast cancer models in preclinical studies Balancing efficacy with potential systemic toxicity due to broad roles of KATs [ 103 ]

BET inhibitors are one of the most studied types of new epi-drugs, but their application in real life has shown that they have both promise and problems. Mechanistically, BET inhibitors operate by competing with BET proteins, mostly BRD4, for the acetyl-lysine recognition pockets, which pushes them out of chromatin [ 104 ]. This stops the positive transcription elongation factor b (P-TEFb) and other co-activators from coming together, which quickly and preferentially turns off important oncogenes, especially MYC , in different types of blood cancers and NUT midline carcinoma [ 105 ]. A defining feature of BETi action is their selective targeting of super-enhancers—large groups of enhancers that control the expression of genes that determine cell identity, including many oncogenes. This may explain why they work as medicines [ 106 ].

Even though there is strong preclinical evidence, clinical trials with BETi monotherapy have produced mixed results and limited effectiveness. Some hematologic malignancies have demonstrated responses; however, outcomes in solid tumors have been predominantly unsatisfactory. There are a number of reasons for this. Dose-limiting toxicities, especially thrombocytopenia, gastrointestinal issues, and fatigue, have made it impossible to give doses high enough to completely block the target [ 107 ]. Additionally, swift development of resistance and the failure to maintain MYC suppression in various contexts have been noted. Kinome reprogramming is one of the crucial ways that cells can resist BET inhibition; the cells will activate the receptor tyrosine kinases and MAPK/ERK and PI3K/AKT pathways that promote oncogenic transcription independently of BRD4 [ 108 ]. Surprisingly, opposing effects on broad transcription have also been reported: while BETi inhibit many protein-coding genes like MYC , they may also cause a global increase in total RNA synthesis by increasing highly transcribed non-polyadenylated RNAs (e.g., histone genes), which may result in transcription-replication conflicts and replication stress [ 109 ]. This dual transcriptional effect highlights the intricacy of BET protein biology.

BET proteins have biological functions that include both promoting cancer and causing inflammation. This makes their inhibitors work in a more complicated way. BET proteins are essential for the expression of pro-oncogenic drivers. Conversely, they serve as principal regulators of the inflammatory response. BET proteins, particularly BRD4, are essential for the expression of NF-κB-dependent pro-inflammatory cytokines [ 110 ]. In myeloproliferative neoplasms (MPN), constitutive JAK2 signaling alters the enhancer landscape, resulting in BRD4-dependent activation of NF-κB signaling in both malignant and non-malignant cells, thereby sustaining a chronic inflammatory state and promoting bone marrow fibrosis [ 111 ]. In this context, BET inhibition diminishes NF-κB signaling and decreases cytokine production in vivo. This anti-inflammatory effect can be therapeutically advantageous, as evidenced by the enhanced efficacy of combining BET inhibitors with JAK inhibitors (e.g., pelabresib with ruxolitinib) in MPN, resulting in diminished symptom burden and reversal of fibrosis. Nonetheless, this identical mechanism may also be responsible for immunosuppressive side effects or context-dependent alterations of the TIME. So, the future of BET inhibitors probably depends on smart ways to combine them. Synergy has been noted with other targeted agents (e.g., enzalutamide in prostate cancer), immunotherapy, and particularly with other epigenetic drugs such as HDAC inhibitors, frequently enabling reduced, less toxic doses of each agent while augmenting antitumor efficacy [ 112 ].

Functional classification of therapeutics

PROTACs targeting histone modifiers

In addition to traditional enzyme inhibitors, novel treatments have been developed to target the epigenetic system in cancer. These strategies offer better specificity, effectiveness, and the ability to get around drug resistance. Some of these methods are proteolysis-targeting chimeras (PROTACs) that break down histone-modifying enzymes, dual-inhibitors that target more than one epigenetic pathway at the same time, and allosteric modulators that use new regulatory sites. These modalities signify a functional advancement in epigenetic drug development, progressing from occupancy-based inhibition to catalytic degradation and multi-target modulation. PROTACs are heterobifunctional molecules that bring an E3 ubiquitin ligase to a specific protein of interest. This causes the protein to be ubiquitinated and then broken down by the proteasome [ 113 ]. This event-driven mechanism has many benefits over conventional small-molecule inhibitors. For example, it can target “undruggable” proteins like transcription factors or scaffolding proteins, get around resistance caused by protein overexpression, and maintain the pharmacological effects going through catalytic degradation [ 114 ]. The creation of the first BRD4-targeting PROTAC was a major step forward in this field. It showed that this bromodomain-containing protein could be broken down quickly and selectively [ 115 ]. Since then, PROTACs have been effectively developed and tested against different histone-modifying enzymes and readers. For example, EZH2-directed PROTACs have been effective in reducing EZH2 and lowering H3K27me3 levels in lymphomas as well as other cancers, possibly providing benefits over chemical inhibitors in specific situations [ 116 ]. In the same manner, PROTACs that target BET family proteins (like BRD2/3/4) and HDACs have been shown in preclinical models to cause stronger and longer-lasting anti-tumor responses than their inhibitory equivalents [ 117 ]. The most advanced PROTACs, especially those that recruit the Cereblon E3 ligase, have begun clinical trials (Phase I-III) for hematological and solid tumors. This is a big step forward in the use of epigenetic degradation strategies [ 118 ].

Although there is immense potential in proteolysis-targeting chimeras, mechanisms of resistance have begun to develop that should be considered. Major mechanisms of PROTAC resistance can be categorized as the loss or mutation of the E3 ligase subunit, the inability to form the ternary complex, increased drug efflux and metabolism, and the reexpression or stabilization of the target protein. Loss or inactivating mutations in Cereblon (CRBN), which has become the most frequent E3 ligase to recruit, will lead to the inability to degrade the target. This mechanism of resistance was first discovered in association with resistance to immunomodulators, such as lenalidomide and pomalidomide, in patients suffering from multiple myeloma [ 119 ]. A mutation at the interface between the target protein and PROTAC, or PROTAC and E3 ubiquitin ligase, will destabilize the three-component complex formation. The consequence will be decreased ubiquitination efficiency without influencing the natural role of the targeted protein. The activation of ATP-binding cassette transporters like P-glycoprotein decreases the intracellular levels of PROTACs due to the molecule’s relatively higher molecular weight [ 120 ].

Designs of next-generation degraders are emerging to counteract such resistance mechanisms using several methods. The use of E3 ligase switching strategies allows for developing degraders that utilize E3 ligases other than CRBN or von Hippel-Lindau, such as MDM2, IAPs, DCAF16, and KEAP1. Pan-E3 ligand strategies have also been envisaged in which E3 ligands are used to engage several ligases at once to avoid resistance [ 121 ]. Trivalent PROTACs involving dual binding of E3 ligases or dual epitope targeting on the target protein increase ternary complex stability and efficiency while making it less likely for resistance-conferring mutations to occur [ 122 ]. The use of covalent PROTACs involves electrophilic warheads that create irreversible or reversible covalent modifications of the cysteine or lysine residue of the target protein or E3 ligase, promoting target engagement and degradation despite mutations that may impair non-covalent interactions [ 123 ]. The antibody-PROTAC conjugates and folate receptor-PROTAC conjugates enhance tumor selectivity, limiting systemic exposure and thus the selective pressure to develop resistance mechanisms [ 124 ]. Finally, molecular glue refers to the thalidomide analogues and aryl sulfonamides that create new protein interactions between a target protein and E3 ligase, regardless of any ligandable pocket within the target protein. Molecular glues help degrade targets once considered undruggable and prevent resistant mutations from interfering with PROTAC binding [ 125 ].

Dual inhibitors

The intricate and compensating characteristics of epigenetic systems have catalyzed the creation of dual inhibitors that simultaneously regulate two separate epigenetic targets. This approach can make treatments more effective, lower the chances of resistance, and deal with the many different causes of cancer. A notable example is the development of dual inhibitors aimed at histone deacetylase 6 (HDAC6) and other proteins pertinent to disease. One reported compound was designed for Alzheimer’s disease, targeting HDAC6 and butyrylcholinesterase; the same conceptual structure is currently being utilized in oncology [ 126 ]. Some of these dual targeting HDAC inhibitors, like EDO-S101, which inhibits HDAC and alkylates DNA; the dual HDAC/PI3K inhibitor CUDC-907; 4SC-202, which inhibits both HDAC and LSD1; and the dual HDAC/EGFR inhibitor CUDC-101, have already begun clinical trials, respectively [ 127 ]. These agents can cause synergistic reactivation of silenced tumor suppressors or apoptosis by inhibiting various nodes in the epigenetic circuitry at the same time, such as a histone-modifying enzyme and a cooperating transcription factor or metabolic enzyme.

Allosteric modulators

Targeting allosteric sites that are unique to an enzyme’s active site could offer an attractive therapeutic approach in the development of highly specific epigenetic drugs. Allosteric modulators can offer enhanced specificity in this regard because they can exploit unique regulatory regions that are not conserved across enzyme families and can offer more nuanced control over protein function [ 128 ]. Recent research into cancer-associated histone missense mutations identified that the oncogenic activity of these mutations can be mediated through allosteric regulation. Mutations such as H2BS64Y and H2BS64F were identified to exhibit long-range allosteric activity that disrupted the normal function of the histone complex, altered H2BK120 ubiquitination levels, and disrupted genome stability [ 129 ]. Consequently, this mechanism highlights the importance of allosteric regulation in nucleosomes and that this mechanism could potentially be targeted using synthetic compounds that can modulate these allosteric sites in histone-modifying complexes or reader complexes. Although the development of synthetic allosteric modulators for epigenetic targets is still in its relative infancy compared to the development of PROTACs, this therapeutic approach could potentially offer attractive therapeutic opportunities in the development of drugs that can target historically difficult targets with minimal off-target effects.

Combination therapies

The limited effectiveness of epigenetic monotherapies, especially in solid tumors, has generated considerable interest in practical combination strategies [ 130 ]. The main rationale for using epigenetic drugs is their ability to reprogram the tumor cell and its microenvironment to overcome resistance mechanisms and increase the effectiveness of conventional and targeted therapies. By reversing epigenetic silencing, modulating the immune system, and inducing replicative stress, these drugs can put the cancer cell in a “sensitized” state, unlocking the synergistic antitumor activity. The synergistic mechanisms for epigenetic drugs in sensitizing tumors to conventional treatments are shown in Fig. 3 .

Fig. 3 Synergistic Mechanisms of Epigenetic and Conventional Therapies. A Epigenetic sensitization to chemotherapy and radiotherapy. The left panel (Monotherapy) illustrates how tumor cells resist genotoxic stress due to functional DNA repair pathways (e.g., homologous recombination, PARP repair) and antioxidant pathways (e.g., Nrf2). The right panel (Combination) illustrates how epigenetic therapies (e.g., BET inhibitors, HDAC inhibitors) target these resistance pathways. They can suppress the expression of DNA repair proteins, induce chromatin relaxation to increase DNA damage, and inhibit antioxidant pathways, resulting in synergistic cell killing. B Epigenetic priming for immunotherapy. The left panel (Monotherapy) illustrates an immunologically “cold” tumor with low MHC-I expression, silenced tumor antigens (e.g., CTAs), high PD-L1 expression, and T cell exclusion/exhaustion. The right panel (Combination) illustrates how epigenetic therapies (e.g., HDAC inhibitors, EZH2 inhibitors) modulate the tumor microenvironment. They can induce MHC-I and antigen presentation, reactivate silenced tumor suppressors and CTAs, and modulate PD-L1 expression. This converts the tumor into an immunologically “hot” tumor, which synergistically responds to ICB, e.g., anti-PD-1/PD-L1, and T cell-mediated tumor lysis. C Simultaneous targeting of oncogenic pathways. The picture on the left (Monotherapy) shows resistance to targeted therapies (such as PI3K/mTOR or MAPK/ERK inhibitors) by pathway compensation and alternative survival signaling. The picture on the right (Combination) shows how the addition of an epigenetic drug (such as an EZH2 inhibitor) can overcome this resistance by suppressing compensatory pathways transcriptionally and preventing epigenetic reprogramming, thus sensitizing the cell to the primary targeted therapy. Abbreviations: BETi, bromodomain and extra-terminal inhibitor; EZH2i, enhancer of zeste homolog 2 inhibitor; HDACi, histone deacetylase inhibitor; ICB, immune checkpoint blockade; PARP, poly (ADP-ribose) polymerase; MHC-I, major histocompatibility complex class I; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; CTA, cancer-testis antigen

As detailed in Sect. 2.5, histone marks like H3K27me3 and H3K4me3 significantly influence the TIME. Utilizing these molecular mechanisms, histone deacetylase inhibitors have proven to enhance MHC class I expression on tumor cells, leading to better cytotoxic T cell response against tumor cells [ 131 ]. Additionally, EZH2 inhibition has demonstrated the reversal of H3K27me3-mediated suppression of chemokines and cancer-testis antigens, which further promotes T-cell recruitment and turns “cold” tumors into “hot” tumors for immune checkpoint blockade treatment [ 132 ]. Blocking both EZH2 and parts of the PI3K/AKT/mTOR pathway has shown a lot of promise because these pathways often work together to make tumors grow and make them resistant to treatment [ 133 ]. Combining EZH2 inhibitors with PARP inhibitors in cancers characterized by DNA repair deficiencies has exhibited synergistic effects, presumably via epigenetic modulation of DNA damage response genes [ 134 ]. The recent emergence of EZH1/2 dual inhibitors, such as valemetostat, has significantly broadened these combinatorial opportunities, evidenced by its clinical effectiveness in aggressive lymphomas characterized by multiple genetic mutations [ 135 ]. A summary of all rational combinations of drugs is provided in Table 4 by dividing them into classes and therapeutic areas.

Table 4 Rational combinations of epigenetic drugs with immunotherapies or targeted agents Epigenetic Drug Class Combination Partner Cancer Type (Examples) Rationale / Mechanism Reference DNMT Inhibitors (e.g., Azacitidine) Immune Checkpoint Inhibitors (e.g., anti-PD-1) NSCLC, MDS/AML, Ovarian Cancer Induces viral mimicry (dsRNA sensing) via ERV reactivation; upregulates tumor antigens, MHC, and PD-L1; reverses T-cell exhaustion. [ 136 , 137 ] HDAC Inhibitors (e.g., Entinostat) Immune Checkpoint Inhibitors (e.g., anti-PD-L1) Breast Cancer, NSCLC, Colorectal Cancer Modulates tumor microenvironment by suppressing myeloid-derived suppressor cells (MDSCs); enhances antigen presentation; upregulates PD-L1. [ 138 ] EZH2 Inhibitors (e.g., Tazemetostat) PARP Inhibitors (e.g., Olaparib) Prostate Cancer, Ovarian Cancer, BRCA-wt Tumors EZH2 inhibition downregulates HR repair genes (e.g., BRCA1 , RAD51 ), inducing HR deficiency and synthetic lethality with PARPi. [ 139 ], Phase I: NCT04846478 EZH2 Inhibitors Immune Checkpoint Inhibitors (e.g., anti-PD-1) Lymphoma, NSCLC, Bladder Cancer Represses the development and function of immunosuppressive cells; promotes T-cell chemokine expression and infiltration; reverses acquired resistance to immunotherapy. Phase I/II: NCT04624113 [ 140 ], BET Inhibitors Immune Checkpoint Inhibitors (e.g., anti-PD-1) Myeloproliferative Neoplasms, Prostate Cancer Suppresses expression of key oncogenes (e.g., MYC); modulates NF-κB signaling and reduces pro-inflammatory cytokine production; alters PD-L1 expression. [ 141 , 142 ], Phase I: NCT05422794 LSD1 Inhibitors Immune Checkpoint Inhibitors (e.g., anti-PD-1) Small Cell Lung Cancer (SCLC), AML Blocks LSD1-mediated silencing of enhancers of immune genes; promotes differentiation; increases tumor immunogenicity. [ 143 ]

Systematic screening methods have found some notable synergistic combinations. A thorough screening of a chemical library containing 2,697 compounds revealed that anti-microtubule agents, including vincristine, demonstrated the most potent synergistic anticancer effects when paired with the BET bromodomain inhibitor JQ1 in neuroblastoma models [ 144 ]. The mechanistic foundation of this synergy entails BET inhibition inducing cell cycle arrest at the G2/M phase, thereby augmenting the cytotoxic effects of microtubule-targeting agents. Also, quinone-containing compounds, like some anthracycline chemotherapies, worked very well with BET inhibitors by blocking the Nrf2-antioxidant signaling pathway. Cancer cells usually turn this pathway on to protect themselves from oxidative stress caused by chemotherapy. As a BET inhibitor, JQ1 also stopped human gastric cancer cells from growing and spreading by turning off the RUNX2/NID1 signaling pathway. It induced global site-specific chromatin remodeling in the genome of GC cells, resulting in increased site inaccessibility [ 145 ]. A lot of clinical trial data backs up the clinical translation of these findings. For example, vorinostat with carboplatin/paclitaxel for ovarian cancer, panobinostat with decitabine/temozolomide for melanoma, and valproic acid with different chemotherapy regimens for different types of cancer. The most clinically advanced of these combinations involves the simultaneous use of DNMTi and HDAC inhibitors, which target different ways of silencing genes. Preclinical studies have shown that DNMT inhibitors may lead to hypermethylated tumor suppressor genes to be expressed again. HDAC inhibitors make this effect stronger by relaxing chromatin at these loci [ 146 ]. Although there is substantial experimental evidence supporting the use of DNA methyltransferase inhibitors and histone deacetylase inhibitors together, therapeutic resistance is a major barrier. Mechanisms leading to resistance involve activation of alternate epigenetic silencing systems, including increased deposition of H3K27me3 by EZH2 or H3K9me3 by SETDB1 in the absence of global DNA hypomethylation and histone hyperacetylation, metabolic adjustments to ensure adequate production of the universal methyl donor S-adenosylmethionine and acetyl-CoA, and triggering an epithelial-mesenchymal transition to become tolerant to drugs [ 147 , 148 ]. Resistance can be overcome through triple epigenetic combination approaches that target DNA methylation, histone deacetylation, and histone methylation to avoid repressive marks as compensation; triple combination approaches with an EZH2 or LSD1 inhibitor in preclinical models of acute myeloid leukemia and ovarian cancers have shown to effectively block silencing in reactivated tumor suppressor genes [ 149 – 151 ]. Interruption therapies based on the relatively slow dynamics of epigenetic remodeling are possible since they permit normal tissue restoration while still applying drug pressure to cancer cells. Moreover, incorporating metabolic blockers such as methionine restriction through diet or methionine adenosyltransferase 2 A inhibition via drugs such as AG-270 can lead to depletion of S-adenosylmethionine, which is necessary for resistance [ 152 ].

A combination of methods should be recommended to experimentally test the mechanisms behind the resistance. For instance, whole-genome epigenomic analysis based on sequencing of ChIP for H3K4me3, H3K27me3, H3K9me3, and H3K27ac, WGBS for DNA methylation, and ATAC-seq for chromatin accessibility, needs to be conducted at baseline, at the maximal response stage, and at the resistance stage. Lineage tracking by using lentivirus barcode tagging along with single-cell RNA-seq and single-cell ATAC-seq may help differentiate pre-existing resistant clones from de novo epigenetic changes acquired resistance [ 153 ]. Genes that induce resistance when inhibited or induced by pooled CRISPR inhibition and CRISPR activation epigenome screens for all epigenetic modifiers can be identified [ 154 ]. The metabolic activity using carbon-13 glucose, glutamine, and serine can trace methylation and acetylation processes in drug sensitive and resistant cells [ 155 ]. Finally, patient derived xenografts or organoids in drug treatment can provide clinically important insights into mechanisms of resistance.

In addition to combinations of DNA methylation and histone modification, new strategies are targeting several histone modifications at once. For instance, the combination of EZH2 inhibitors and BET bromodomain inhibitors has shown synergistic effects in preclinical cancer models [ 156 , 157 ]. Researchers found that BET and EZH2 inhibitors stopped MYC from being activated, which led to a synergistic effect on stopping the growth and cloning of metastatic prostate cancer cells [ 158 ]. The combination of various classes of histone-modifying enzyme inhibitors—such as HAT inhibitors with HDAC inhibitors—remains to be investigated as a strategy to more accurately regulate the epigenetic state of cancer cells [ 159 ]. Such multi-epigenetic strategies are a reflection of the realization that cancer epigenomes are maintained by complex and redundant regulatory systems that may need to be targeted simultaneously.

Translational perspectives and cross-disciplinary insights

Clinical trials and challenges

Barriers to clinical translation

The translation of epigenetic therapies from promising preclinical models to the clinic has been a journey of both encouraging successes and sobering challenges. Although epi-drugs have established a firm foothold in hematological malignancies, their use in solid malignancies has been more restricted, thereby emphasizing the need to understand and overcome the barriers to their efficacy [ 160 ]. A significant obstacle is extensive tumor heterogeneity, which manifests at various levels. Intratumor heterogeneity denotes subpopulations of neoplastic cells exhibiting unique molecular characteristics within a singular tumor [ 161 ]. This diversity is a significant cause of treatment failure, as epi-drugs may only effectively target a vulnerable subset, allowing resistant clones to multiply and cause relapse [ 162 ]. Moreover, bulk-tissue molecular profiling, which assesses an average across all cell types in a sample, may conceal significant cell-type-specific epigenetic modifications that facilitate cancer progression [ 163 ]. A new computational method called cell-type-specific combinatorial clustering (CELTYC) has shown that breaking down the epigenetic landscape by cell type can help doctors better predict how well a patient will do with liver or kidney cancer. This means that future clinical trials may need to take this complexity into account to find patient groups that really respond to treatment [ 163 ].

Another major problem is that there aren’t enough validated predictive biomarkers. Some epi-drugs have clear biomarkers, like EZH2 mutations for tazemetostat and MTAP deletion for PRMT1 and PRMT5 inhibitors. However, these are the only ones [ 164 , 165 ]. It is still not clear which patients will benefit the most from most epi-drugs, especially when they are used with other drugs. The advancement of epigenetic biomarkers, such as distinct DNA methylation patterns (e.g., MGMT promoter methylation correlating with temozolomide response in glioblastoma) or histone modification signatures, shows potential for patient stratification [ 166 ]. The amalgamation of multi-omics technologies is essential for discerning these fundamental drivers from intricate epigenetic networks and for creating blood-based liquid biopsies for non-invasive monitoring [ 167 ].

To address the critical need for predictive biomarkers, several strategies have emerged to create a composite epigenetic biomarker that utilizes the histone modification profile, the DNA methylation pattern, and the chromatin accessibility landscape. The method employed in practice involves the co-profiling of histone modifications, DNA methylation, and chromatin accessibility on one single tumor sample. Histone modification profiles, such as H3K27me3, H3K27ac, and H3K4me3, are characterized using ChIP-seq technology, but recently the CUT&RUN (Cleavage Under Targets and Release Using Nuclease) and CUT&Tag (Cleavage Under Targets and Tagmentation) technologies are also being employed [ 168 ]. Genome-wide analysis of DNA methylation levels is performed by whole-genome bisulfite sequencing or the use of reduced representation bisulfite sequencing or Illumina Infinium MethylationEPIC BeadChip in clinical samples with low DNA availability [ 169 ]. Chromatin accessibility maps are generated by ATAC-seq that can be carried out even in cell counts as low as 500 cells [ 170 ]. In clinical samples where heterogeneity within the tumor is a major confounding variable, single-cell multi-omics approaches, which include the use of scCUT&Tag with scBS-seq or scATAC-seq, as well as the 10x Genomics Chromium system that allows for simultaneous profiling of the transcriptome and chromatin accessibility in the same cell, make this possible [ 171 ].

The computational approach used in the development of composite biomarkers involves a number of different steps. The first step is multi-omics data integration, where techniques like Multi-Omics Factor Analysis (MOFA), which detects latent factors that capture the primary sources of variance in the data sets [ 172 ]; iClusterPlus, which uses multiple data sets to detect integrated clusters [ 173 ]; and Similarity Network Fusion, which creates patient similarity networks for individual data sets before fusing them together [ 174 ]. After integration, the selection of features is done using machine learning approaches like LASSO (least absolute shrinkage and selection operator) regression, random forests, or gradient boosting, in order to find the smallest number of epigenetic features that carry maximum prediction value for response to treatment [ 175 ]. The selected features are then merged to form composite scores using approaches like the Machine Learning-derived Epigenetic Model (MLEM) for breast cancer, whereby DNA methylation and histone modification data are integrated into one score that can later be assessed using targeted deep sequencing/qPCR analysis on patient samples [ 176 ]. Such composite scores need validation in independent patient populations as well.

Building predictive biomarkers

These challenges can be met by the move toward the development of a novel approach to epigenetic stratification through the identification of specific subtypes based on genomic and epigenomic markers rather than the organ from which the tumor originates. Mutation-driven epigenetic therapy takes advantage of the presence of certain genetic changes within the tumor that render it sensitive to epigenetic inhibition. Tumors carrying gain-of-function EZH2 mutations, including hotspots such as Y641, A677, and A687 mutations in germinal center B cell-like diffuse large B cell lymphomas and follicular lymphomas, are highly sensitive to EZH2 inhibition through drugs like tazemetostat [ 177 ]. Similarly, MTAP homozygous deletions, found in up to 15% of all tumors, in particular, glioblastoma, pancreatic adenocarcinomas, and mesotheliomas, induce PRMT5 inhibition sensitivity due to synthetic lethality based on methylthioadenosine metabolite accumulation [ 178 ]. Mutations in the ARID1A gene, leading to a shortage of the SWI/SNF chromatin remodelers, suggest the sensitivity of EZH2 inhibitors in ovarian clear cell carcinomas, gastric cancers, and endometrial carcinomas, based on a recognized antagonistic effect of the two complexes and tumor dependence on EZH2 for transcriptional suppression [ 179 ].

Beyond mutations in individual genes, epigenomic marker-based stratification identifies cancers on the basis of a more extensive epigenetic pattern. The CpG island methylator phenotype (CIMP), defined by coordinated methylation of a large number of CpG islands first identified in colorectal cancer, identifies different responses to DNMT inhibitors and is being evaluated prospectively in clinical trials [ 180 ]. Histone modification-based patterns such as comparison of H3K27me3 versus H3K27ac identified using ChIP-seq may predict dependence on PRC2 activity, hence sensitivity to EZH2 inhibition, and/or on super enhancers, hence sensitivity to BET inhibition [ 181 ]. Additionally, the relative abundance of H3K27me3/H3K27ac at the promoter region of established PRC2-targeted genes evaluated using ChIP-seq or targeted CUT&Tag assays of selected PRC2-targeted tumor suppressor genes, like the Hoxa cluster gene, is useful in identifying highly PRC2-dependent cancers and those that are sensitive to EZH2 inhibitors [ 182 ]. Furthermore, the H3K27me3 domains distribution pattern can be used as a marker, where the presence of wide H3K27me3 domains, meaning the spreading of the mark beyond the CpG islands rather than the focal deposition at CpG islands, denotes an EZH2-dependent and inhibitor-sensitive cancer phenotype [ 183 ].

Locus-specific validation for clinical application

Several methods for locus-specific validation of epigenetic biomarker candidates identified using genome-wide approaches can be adopted. ChIP-qPCR allows researchers to explore genomic loci for enrichment of specific histone modifications and is possible with just 10,000 to 50,000 cells. Alternatively, CUT&RUN-qPCR and CUT&Tag-qPCR have been developed as more efficient techniques for clinical studies as they involve minimal number of cells (about 500 to 5,000 cells) and provide a much higher signal-to-noise ratio because of no cross-linking and sonication steps involved [ 184 , 185 ]. Regarding DNA methylation, methylation-sensitive PCR and pyrosequencing are the locus-specific, quantitative methods that have the further advantage of being able to evaluate several CpG sites at once within one specific area in the bisulfite-modified DNA, which is stable in FFPE tissue [ 186 ].

Nonetheless, major challenges exist in the clinical application of such locus-specific approaches. One is the issue of heterogeneous tissue samples, whereby the averaging effect on epigenetic information obtained from tumor, stromal, and immune cells can obscure important changes within different cellular types [ 187 ]. Issues such as sample integrity and volume due to the small amount of material obtainable from core needle biopsy or FFPE block samples pose a challenge to the reliability of results since DNA degradation and protein crosslinking can significantly influence the outcome. Additionally, since epigenetic modification exhibits flexibility, a single snapshot measurement from a biopsy sample collected prior to treatment may fail to capture the dynamic nature of tumor epigenetics [ 188 ]. Moreover, inconsistent protocols and the absence of standard references used between laboratories prevent reproducibility and translation into clinic. Deconvolution methods like EpiDISH and CELTYC, along with the development of single-cell epigenomics, are some strategies that have been adopted to tackle these problems; however, their application into the clinic is still a distant goal [ 163 , 189 ].

Designing biomarker-driven trials

A well-designed translational trial for the combination of an EZH2 inhibitor (tazemetostat) and an immune checkpoint inhibitor (pembrolizumab) should consider four interrelated aspects: biomarker-based patient selection, tumor type selection, lead-in design, and response evaluation beyond standard radiographic assessments.

A biomarker-driven enrichment strategy aims to select a cohort of patients with tumors that are dependent on EZH2, which helps in achieving a greater chance of success. The literature provides examples where synthetic lethality with EZH2 has been achieved by using EZH2 gain-of-function mutations (Y641, A677, A687) in follicular lymphoma and ARID1A mutations in ovarian clear cell carcinoma and gastric cancers [ 177 , 179 , 190 ]. However, relying solely on mutational status has limitations: the prevalence of EZH2 mutations in solid tumors is low (typically 2–5%), and some EZH2 -wild-type tumors exhibit high PRC2 activity driven by upstream oncogenic signaling, such as mutant KRAS or MYC amplification [ 77 , 79 ]. Consequently, functional epigenomic biomarkers including global H3K27me3 levels, the H3K27me3/H3K27ac ratio at PRC2 target genes, or broad H3K27me3 domain patterns may offer complementary predictive value [ 181 – 183 ]. A pragmatic approach is to enroll patients based on either mutational status (e.g., EZH2 or ARID1A mutations) or elevated H3K27me3 expression by immunohistochemistry, with pre-specified subgroup analyses to compare response rates across enrichment criteria.

It is mechanistically sound to choose specific cancer types, such as small cell lung cancer, ovarian clear cell carcinoma, triple-negative breast cancer, and ARID1A mutant endometrial and gastric cancers, due to the presence of preclinical data. The first type of cancer has increased EZH2 and H3K27me3 levels, and EZH2 inhibition improves chemotherapeutic response by derepression of SLFN11 [ 191 ]. EZH2 dependency in ovarian clear cell carcinoma and ARID1A -mutated gastric cancers arises due to the loss of function of the SWI/SNF complex [ 190 , 192 ]. Overexpression of EZH2 occurs in triple-negative breast cancer, which results in gene silencing and induction of stemness; furthermore, inhibition of EZH2 promotes immune response against tumor cells [ 132 , 133 ]. However, one important consideration is that most of this evidence is derived from preclinical xenograft models, which might not accurately represent the immune microenvironment of human tumors. Additionally, there is notable diversity in the immune contexture of different types of tumors; for instance, small cell lung cancer is usually an immune “cold” tumor due to the lack of T cell infiltration, while some ARID1A-mutant gastric cancers are characterized by high mutational load and existing immune infiltration.

Regarding the timing of the trials, the rationale for a 14 to 21 day lead-in treatment period with tazemetostat monotherapy prior to the first pembrolizumab dose is based on the mechanism of action. For EZH2 inhibition to be effective, it will take time to deplete pre-existing H3K27me3 marks (half-life of 48 to 72 h), re-express Th1-related chemokines, CXCL9 and CXCL10, and attract CD8 + T cells [ 193 ]. A similar type of lead-in design is also being used in current trials for EZH2 inhibitors combined with ICIs ( NCT04624113 , NCT04846478 ). The continuous dosing regimen of tazemetostat at 800 mg BID (the FDA approved dose) is preferred over the intermittent dosing regimen because of the slow turnover of histone methylation [ 101 ]. Immune-mediated adverse event management should be guided by the standard ICI toxicity guidelines that recommend the administration of corticosteroids for all events of grade 2 and above. However, prophylaxis is not generally recommended since it could reduce the effectiveness of the anti-tumor immune response.

The choice of endpoints for response assessment requires careful consideration. Despite being the accepted primary endpoint in phase II studies, objective response rate based on RECIST v1.1 could fail to recognize atypical responses such as pseudoprogression, due to immune infiltration, which could be incorrectly classified by the criteria. Therefore, immune-related response criteria (iRECIST) need to be used as a secondary endpoint. More importantly, pharmacodynamic markers would include the degree of decrease in H3K27me3 modification, determined by CUT&Tag-qPCR using on-treatment tumor biopsies, and the fold increase in the expression of CXCL9, CXCL10, and CCL5 by RNAscope. These need to be included as co-primary or key secondary endpoints to prove the mechanism. Changes in promoter DNA methylation of PRC2 targets in circulating tumor DNA, determined by targeted bisulfite sequencing, could be considered an exploratory surrogate endpoint [ 167 ]. It would be important to validate the mechanistic hypothesis and inform future phase III trial design by proving the correlation between pharmacodynamic markers and objective response rate.

Natural products as epigenetic modulators

Natural products, which are obtained from plants, fungi, and marine organisms, are a promising and very rich source of epigenetic modulators for cancer prevention and treatment [ 194 ]. The attraction towards these compounds is based on their varied chemical structures and their potential to target various aspects of the epigenetic system, such as DNA methylation, histone modifications, and microRNA expression [ 195 ]. The fact that epigenetic modifications are reversible makes them a highly attractive target for therapeutic intervention, and natural compounds have shown great promise in resetting dysfunctional epigenetic marks in cancer cells [ 196 ]. These bioactive compounds have the ability to reverse the epigenetic silencing of tumor suppressor genes, suppress the proliferation of cancer cells, trigger apoptosis, and reverse chemoresistance, as shown in various preclinical studies [ 197 ].

Some major categories of natural products have been extensively explored in the context of their ability to modulate epigenetic functions. The most prominent of these are the polyphenolic compounds, including curcumin derived from turmeric and resveratrol derived from grapes and berries. Curcumin is an all-around epigenetic modulator that can inhibit both HATs and HDACs while also modulating the activity of enzymes that regulate both histone methylation and demethylation processes [ 198 ]. In the same way that curcumin does, another compound derived from grapes and berries, named resveratrol, is also known to activate sirtuins, a class of NAD+-dependent HDACs; downregulate the expression of epigenetic writers like EZH2 and PRMT5 ; and inhibit Class I/III HDACs, leading to the reactivation of tumor suppressors like p53 through changes in both histone H3 acetylation and methylation marks [ 199 ]. Other notable compounds include EGCG derived from green tea, which can directly inhibit DNMTs, while compounds like anacardic acid and garcinol are potent inhibitors of HATs [ 200 ]. The epigenetic targets, mechanisms, and status of development of these and other major natural compounds are listed in Table 5 .

Table 5 Natural compounds with histone-modifying activity in cancer Natural Compound Natural Source Primary Epigenetic Target(s) Mechanism of Action in Cancer Preclinical Evidence Reference 3,3’-Diindolylmethane (DIM) Cruciferous vegetables DNMT inhibitor; HDAC inhibitor Promoted the degradation of Class I HDAC proteins, which lead to increased p21WAF1 and p27KIP2. Reduced DNA methylation by downregulating DNMTs, thereby reversing the silencing of Nrf2. In vitro, suppressed HDAC activity resulted in cell cycle arrest and apoptosis in prostate and colon cancer cells. In vivo, suppressed the incidence of tumorigenesis and metastasis, and reactivated the expression of phase II detoxifying enzymes. [ 201 – 203 ] Anacardic Acid Shell liquid of the cashew nut ( Anacardium occidentale ) HAT Inhibitor (p300/CBP, Tip60) Inhibited the acetyltransferase activity of p300/CBP and Tip60, leading to reduced histone acetylation and suppression of oncogenic transcription factors. Suppressed tumor growth and induced apoptosis in preclinical models; Sensitized cancer cells to radiation and chemotherapy. [ 204 – 206 ] Apigenin Parsley, chamomile, celery DNMT inhibitor; HDAC inhibitor Downregulated DNMT1, 3a, and 3b, reducing methylation and reactivated silenced genes; Increased histone acetylation, which promotes the expression of p21WAF1 and Bax. In vitro, reduced activity and expression of HDAC resulted in elevated Bax/Bcl-2 ratios and p53-mediated growth inhibition. In vivo, reduced tumor volume and weight correlated with reduced activity of HDAC in the tumor and restored levels of p21. [ 207 ] Astaxanthin Microalgae Haematococcus pluvialis DNMT inhibitor; HDAC inhibitor Reduced the expression of DNMTs, leading to the demethylation of CpG islands of GSTP1 and Nrf2. Promoted histone acetylation (e.g., H3ac and H4ac). Reduced cell viability and induced G0/G1 cell cycle arrest through the modulation of DNA methylation and histone acetylation in vitro. In vivo studies showed that it enhanced the cytotoxicity of doxorubicin through epigenetic immunomodulation and elevated Bax/Bcl-2 ratios. [ 208 – 210 ] Berberine Berberis species (e.g., goldenseal) DNMT inhibitor; HDAC inhibitor Downregulates the expression of DNMT1 and HDACs, which leads to the restoration of tumor suppressor gene expression by demethylating the promoter and hyperacetyling the histones. Inhibited the interaction between SP1 and the DNMT1 promoter to inhibit tumor growth. The growth of cancer cell lines was inhibited by inducing cell cycle arrest in the G0/G1 or G2/M phase and activating mitochondrial pathways of apoptosis. The in vivo model showed reduced tumor volume and metastasis that correlated with reduced intratumor HDAC activity and increased global DNA methylation stability. [ 211 – 214 ] Curcumin Turmeric (Curcuma longa) HAT/HDAC Inhibitor; HMT/KDM Modulator Inhibits p300/CBP HAT activity and Class I HDACs; modulates HMTs (e.g., for H3K4, H3K9, H3K27) and HDMTs; induces global histone acetylation changes and reactivates tumor suppressors. Induces cell cycle arrest and apoptosis in various cancer cell lines (e.g., leukemia, colorectal); shows anti-proliferative and anti-inflammatory effects in vivo. [ 215 , 216 ] Epigallocatechin-3-gallate (EGCG) Green tea DNMT/HAT Inhibitor Directly inhibits DNMT1 activity, leading to DNA demethylation and gene reactivation; modulates HAT activity (e.g., p300), influencing histone acetylation marks. Reverses hypermethylation of tumor suppressor genes in vitro; inhibits growth in various cancer models (e.g., breast, colon). [ 217 , 218 ] Garcinol Garcinia indica HAT Inhibitor (p300/CBP); Histone Kinase Inhibitor Functions as a potent dual inhibitor of p300 and PCAF HATs; also reported to inhibit histone phosphorylation. Demonstrates pro-apoptotic and anti-proliferative effects in cancer cell lines and xenograft models. [ 219 – 221 ] Resveratrol Grapes, red wine, berries SIRT1 Activator; HDAC/EZH2/PRMT5 Inhibitor Activates the deacetylase SIRT1; suppresses expression of EZH2 and PRMT5, reducing H3K27me3 and H4R3me2s; inhibits Class I/III HDACs, increasing H3 acetylation; restores expression of tumor suppressors (e.g., p53). Inhibits proliferation in breast and prostate cancer models; anti-angiogenic and pro-apoptotic effects in vivo. [ 222 – 224 ]

A very active area of research has been the investigation of the ability of natural products to interfere with the activity of enzymes that regulate the methylation of histones. These compounds include green tea polyphenols, flavonoids, curcuminoids, and isothiocyanates, all of which can regulate the activity of key enzymes that play a role in the methylation or demethylation of lysine or arginine residues of histones [ 225 ]. The key enzymes that have been the focus of this research include EZH2, an enzyme that catalyzes the formation of the repressive H3K27me3 modification, and LSD1, an enzyme that catalyzes the removal of the activating H3K4me3 modification [ 226 ]. The inhibition of these enzymes can result in the regulation of gene expression in cancer cells, thereby leading to reduced cell proliferation, migration, and increased apoptosis in cancer cells [ 227 ].

However, despite their promising preclinical antitumor activities, the clinical application of natural epigenetic modulators is hindered by a number of challenges. First, natural epigenetic modulators have poor bioavailability. Many natural agents, such as curcumin and resveratrol, exhibit poor solubility in water, instability in the gastrointestinal environment, and undergo first-pass metabolism, resulting in extremely poor circulation of the active compound in the body [ 228 ]. In addition, natural agents are known to be pleiotropic agents, which, although beneficial in a synergistic manner, make it difficult to establish the exact mechanism of action. To address these challenges, new and advanced strategies are being explored. Nanotechnology, in new drug delivery systems, is a promising tool for improving the antitumor activities of natural epigenetic modulators [ 229 ]. Nanoparticles, such as liposomes and polymeric nanoparticles, can be used to deliver natural agents, and this is advantageous because it improves solubility, stability, and antitumor activity through enhanced targeting and controlled release of the compound, which is a significant improvement over conventional delivery [ 230 ]. In addition, the synthesis of semi-synthetic analogs, such as dimethoxycurcumin, is a new and promising strategy to improve stability and potency, and retain epigenetic modulating activities [ 231 ].

In summary, natural products are invaluable resources for histone-modifying enzyme modulators and epigenetic regulators. Although there are still issues regarding bioavailability and understanding of mechanisms, approaches such as structural optimization, advanced delivery systems, and combination therapies are promising ways to overcome these challenges and unlock their potential for the benefit of cancer patients.

Integrative epigenetic frameworks

This intricacy of cancer epigenetics is not limited to specific epigenetic modifications but extends to a complex interplay between epigenetic layers, where histone modifications, DNA methylation, non-coding RNAs, and chromatin remodeling factors communicate and coordinate to modulate and regulate gene expression. This integrative epigenetic landscape, which describes the main axes of epigenetic crosstalk, is depicted in Fig. 4 . This crosstalk between epigenetic modifications is perhaps most vividly exemplified by the cooperative regulation of tumor suppressor gene silencing, where histone modifications, e.g., H3K27me3, which is catalyzed by PRC2, provide a binding site for DNMTs that catalyze hypermethylation of tumor suppressor gene promoters, thereby stably and heritably silencing genes [ 232 ]. Conversely, DNA methylation can modulate and regulate histone modifications, e.g., by binding methyl-binding proteins such as MeCP2, which can subsequently recruit HDACs and other chromatin remodeling factors that catalyze epigenetic gene expression regulation [ 233 ].

Fig. 4 A Unified Model of Epigenetic Crosstalk Driving Cancer Plasticity. A Core integrative framework and crosstalk mechanisms. Major epigenetic interactions are depicted: (1) DNA methylation-histone crosstalk: PRC2 deposits H3K27me3, recruiting DNMTs for synergistic gene silencing. Simultaneously, MeCP2 binds methylated DNA to recruit HDACs. (2) Non-coding RNA regulation: Long non-coding RNAs (e.g., XIST) and microRNAs modulate the expression and activity of epigenetic complexes, while RNA modifications (e.g., m6A) regulate their stability. B Functional consequence: Tumor heterogeneity and plasticity. The integrated epigenetic system allows for dynamic, reversible transitions between different cell states (e.g., proliferative, invasive, drug-tolerant persister). This plasticity is the hallmark of CSC maintenance, which is regulated by PRC2/BMI1. Abbreviations: PRC2, Polycomb Repressive Complex 2; EZH2, enhancer of zeste homolog 2; DNMT, DNA methyltransferase; MeCP2, methyl-CpG-binding protein 2; HDAC, histone deacetylase; lncRNA, long non-coding RNA; miRNA, microRNA; m⁶A, N⁶-methyladenosine; CSC, cancer stem cell; EMT, epithelial-mesenchymal transition

In addition to the traditional interplay between DNA and histone modifications, ncRNAs play a pivotal role as integrators and master regulators in this regulatory circuit. LncRNAs have been shown to act as modular scaffolds that physically bring histone-modifying enzymes together with specific genomic loci. For example, the lncRNA HOTAIR acts as a scaffold that brings the PRC2 complex to target genes, leading to the deposition of H3K27me3 and silencing of metastasis suppressors [ 234 ]. Similarly, microRNAs (miRNAs) also play a role in epigenetic regulation by modulating the levels of epigenetic enzymes. For example, miRNAs targeting DNMT3B or HDAC4 can indirectly modulate global methylation and acetylation levels, providing another layer of post-transcriptional regulation of the epigenome [ 235 ]. The relatively recent discovery of the epitranscriptome, or post-transcriptional modifications of RNA, such as N6-methyladenosine (m6A), provides a new layer of complexity to this regulatory framework. The m6A modification of ncRNAs has been shown to modulate their stability and function. For example, m6A modification of the lncRNA XIST is essential for its function in X-chromosome inactivation [ 236 ]. On the other hand, epigenetic modifications can regulate the transcription of ncRNA genes, illustrating the complex reciprocity of this regulatory framework [ 237 ].

The functional outcome of this integrated epigenetic system is the creation of a deep heterogeneity and plasticity of tumor cells. This system enables the dynamic and reversible transition between different cell states, like from a proliferative state to an invasive or drug-tolerant persister state, without the need for genetic mutations [ 238 ]. Cancer stem cells (CSCs), a subset of cancer cells that initiate tumor formation and are also responsible for therapeutic resistance, are a major reflection of this plasticity. The maintenance of these CSCs is extremely epigenetics-dependent, often mediated by a particular epigenetic program, which is frequently controlled by complexes such as PRC2 and BMI1, suppressing differentiation genes [ 239 ]. Moreover, the interplay between DNA repair mechanisms and the epigenetic system also plays a role in this dynamic system. DNA damage can trigger a specific chromatin modification, and vice versa, the existing epigenetic status of a region determines the pathway of DNA repair, as observed in CSCs, where a particular chromatin structure can improve the efficiency of DNA repair and generate resistance [ 240 ].

Multi-omics approaches for single cells have recently been developed as useful techniques to discover and analyze DTPs (drug-tolerant persisters), which are rare subclones characterized by their epigenetic state and drug insensitivity that can reverse and develop acquired drug resistance [ 241 ]. To discover DTP cells, the protocol includes the simultaneous analysis of the transcriptional profile, chromatin accessibilities, and histone modification profiles of the same individual cells with the help of combinatorial barcodes or split-pool strategies. Technology platforms like the 10x Genomics Multiome platform allow for the simultaneous acquisition of scRNA-seq and scATAC-seq data, whereas CUT&Tag methods could be modified to analyze two or three histone marks in single cells at the same time. This includes the identification of both the repressive H3K27me3 and the active H3K27ac modifications [ 242 ].

The hallmark features of DTPs are determined using computational approaches based on the following characteristics: cell cycle arrest through the downregulation of proliferation genes like MKI67 and PCNA ; upregulation of genes associated with stemness and lineage plasticity, including high levels of SOX2 , NANOG , and CD44 ; specific chromatin accessibility maps in enhancer and promoter regions of genes associated with drug resistance and survival; and histone modifications, especially the increased presence of H3K27me3 marks at pro-apoptotic gene promoters and H3K4me3 marks at stemness gene promoters. The use of computational approaches like Monocle 3, Slingshot, or RNA velocity to analyze the gene expression and chromatin accessibility data allows the reconstruction of the epigenetic pathway in the process of tumor cell transformation from naïve states through the DTP phase to resistance state [ 243 , 244 ]. With the integration of endogenous mtDNA mutations used as lineage barcodes or exogenous lentivirus-based lineage tracing, clonal relationships between DTP cells and subsequent resistant lineages can be determined [ 245 ]. For example, studies on non-small cell lung cancer resistant to EGFR inhibitors have used scATAC-seq to profile a DTP cell subpopulation exhibiting an open chromatin state of enhancers for the transcription factor HOPX, which drives neuroendocrine differentiation into small cell carcinoma [ 246 ].

Discussions and conclusions

One of the important concepts of the review is the difference between particular histone-modifying enzyme inhibitors (e.g., EZH2 in lymphomas), which allow a “precision medicine” approach to cancer therapy, and broad-spectrum histone-modifying enzyme inhibitors (e.g., pan-HDAC inhibitors), which have more toxic side effects. It also demonstrated the value of a “pan-cancer” approach to histone modifications in cancer development: although certain mechanisms, such as PRC2 dysregulation, are common in cancer development, they cannot be disentangled from cellular context. The strengths in the histone modifications in cancer development are in the mechanistic understanding from a broad concept to a more precise concept of how histone modifications interact with DNA methylation, non-coding RNAs, and chromatin remodelers in sustaining cancer development. Concurrently, the therapeutic armamentarium has moved from the initial DNMTs and HDAC inhibitors to include agents targeting BET, DOT1L, and LSD1 proteins, in addition to new modalities like PROTACs and dual inhibitors. These developments notwithstanding, there are also considerable hurdles in terms of translation. Achievement of clinical success, especially in the context of solid tumors, remains suboptimal. These can be explained by several key factors: dose-limiting toxicities, tumor cell plasticity that facilitates adaptive resistance mechanisms, and an alarming paucity of reliable biomarkers. The biggest paradox in this context is that while epigenetic profiles are constantly evolving in tumors, these interventions do not result in sustained remissions due to the ability of tumor cells to utilize alternative mechanisms for sustaining malignancy. To fully exploit the clinical potential of epigenomic targeting in cancer, subsequent studies must prioritize a series of strategic objectives. First, it will be important to find strong predictive biomarkers, such as global histone marks, specific DNA methylation profiles, or mutations in epigenetic regulators, in order to group patients. Second, it will be necessary to use combination therapies. Combinations with immunotherapy will not only focus on the TME but may also enhance immune recognition. Conversely, combinations with metabolic inhibitors will specifically target the metabolite pools necessary for chromatin regulation. Third, we will need to use the latest technologies, like single-cell multi-omics, to figure out how different types of cells are in tumors and how flexible persister cell populations are in terms of their epigenetics. Finally, therapeutic windows will need to be improved by using new delivery systems, like nanoparticles, to make targeting more precise and cut down on off-target effects.

In conclusion, histone modifications, including histone acetylation, methylation, phosphorylation, and newly identified modifications such as lactylation and crotonylation, play important roles as histone modification dysregulation is associated with tumorigenesis in various forms of cancer. Although there have been notable successes in the therapeutic targeting of histone modification dysregulation in cancer, including in hematological malignancies, there are still many hurdles to be overcome, including drug resistance, heterogeneity, and efficacy in solid tumors. However, by applying precision medicine approaches, rational drug combinations, and new technologies such as PROTACs, the full therapeutic potential of the cancer epigenome will be realized.

Publisher’s note

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Pengde Lu and Yau-Tuen Chan contributed equally to this work.

Acknowledgements

All figures are created in BioRender ( https://BioRender.com ).

Authors’ contributions

NW conceived the idea and revised the manuscript; PL and YTC collected and analyzed the data and drafted the manuscript; CFK, QL, ZJ, LX, ZF, HY, JZ, YX, TLF and CMC revised the manuscript.

Funding

This work receives the funding support for studentship of Mr. Pengde Lu from Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program launched by Innovation and Technology Commission, The Government of Hong Kong Special Administrative Region of the People’s Republic of China (Project Code: RPG-20250101). This work was also supported by the Research Grant Committee of Hong Kong (Project Code: 17119621, 17111424, 17120225), the Health and Medical Research Fund (Project Code: 21222151, 19201591 and 15162961), the Innovation and Technology Fund (Project Code: PRP/028/22FX & PRP/029/24FX), and Young Qihuang Scholar of the “Tens of Millions” Talent Project of China (Ning Wang).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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