Exploring viral mimicry combined with epigenetics and tumor immunity: new perspectives in cancer therapy.

Introduction

Viral mimicry

Viral mimicry is a cellular state of active antiviral response induced by endogenous stimuli rather than exogenous viral infection that affects tumor immunity by activating endogenous retroviruses (ERVs) that are epigenetically silenced and inducing an interferon response 1 - 3 . In this process, activation of ERVs leads to the formation of double-stranded RNA (dsRNA), which can be sensed by pattern recognition receptors (PRRs) such as the cytosolic melanoma differentiation-associated gene 5 (MDA5), which further activates the mitochondrial antiviral signaling protein (MAVS) pathway 4 , 5 . In addition, TANK binding kinase 1 (TBK1), a central node protein involved in multiple intrinsic immune signaling pathways, activates both NF-κB and IRFs and is a critical protein kinase in the body's resistance to infection 6 , 7 . In viral mimicry response, TBK1 promotes interferon regulatory factor 7 (IRF7) dimerization and translocation to the nucleus by phosphorylating IRF7 to form an active transcriptional complex, which in turn initiates type I and type III interferon responses, stimulates cytokine production, and enhances the body's antiviral, antimicrobial, antitumor, and immunomodulatory functions 8 , 9 (Figure 1 ).

Epigenetics

Cancer has long been regarded as a hereditary disease, but with advances in epigenetic research, there is growing evidence of the important role of epigenetic alterations in tumorigenesis and progression 10 , 11 . Thus, cancer can be regarded not only as a hereditary disease, but also as an epigenetic disease 12 . The central concept of epigenetics is that epigenetic modifications of chromosomes can lead to persistent changes in gene expression, although the DNA sequence itself is unaltered, and these changes can be transmitted to offspring through cell division. In addition, classical mechanisms of epigenetic inheritance include alterations in DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA-mediated gene regulation 12 , 13 . These epigenetic abnormalities play a crucial role in the stability of chromatin structure, the regulation of gene expression, and the maintenance of basic cellular physiological functions, especially in the process of tumorigenesis and progression, and disruptions in epigenetic mechanisms are closely related to tumor formation and treatment resistance 14 . Therefore, epigenetics is expected to be an attractive therapeutic target in cancer treatment. With the deepening of oncology research, researchers have found an increasing role for epigenetics in aspects such as diagnosis and prognosis of tumors 15 . The most widely used epigenetic therapies in cancer treatment are small molecule inhibitors (i.e., demethylating drugs) that use DNA methyltransferase (DNMT). Notably, previous reports have indicated that DNA methylation prevents the activation of retroviral progenitors in drug-resistant cells and that using hypomethylating drugs can reactivate ERVs and inhibit the growth of tumor cells 16 , 17 . These studies suggest that viral mimicry could enhance the therapeutic effect on cancer by combining it with epigenetic therapies.

Tumor immunity

Tumor immunotherapy aims to harness the body's natural immune system to activate and enhance its ability to attack tumors. By activating specific immune cells, such as T-cells and natural killer cells, and by proliferating the antitumor immune response in the body, the therapy can direct the body's immune system to recognize and destroy tumor cells 18 - 20 . Its basic principle lies in breaking the evasion mechanism of the tumor cells against the immune system and reawakening the immune cells so that they can recognize and attack the tumor cells, thus clearing the tumor 21 . Tumor immunotherapy has specific therapeutic effects for cancer patients with few side effects and is listed as one of the four major tumor treatment techniques, together with surgery, radiotherapy and chemotherapy 22 , 23 . The origins of tumor immunotherapy can be traced back to 1893, when Cloey discovered that sarcoma patients infected with Streptococcus pyogenes experienced tumor regression following surgery. Thereafter, he further explored the mechanism and, for the first time, used attenuated bacterial mixtures to stimulate the immune system to enhance the patient's resistance to disease, a discovery that laid the groundwork for the emergence of modern immunotherapy and provided important insights into subsequent therapeutic strategy exploration 24 , 25 . Subsequently, with a large number of studies, the mechanisms of tumor immunity have been better understood, and tumor immunotherapy has been classified into four modalities: non-specific immune stimulation, immune checkpoint blockade, tumor vaccines, and overdose immune cell therapy 26 . In addition, recent studies have revealed that the expression of ERVs can trigger the activation of innate immune receptors, thereby initiating an immune response against viral, a process that may induce tumor cell death 2 , 27 , 28 . This discovery has led to new research directions in cancer treatment and may provide a theoretical basis for developing more effective immunotherapy strategies in the future.

1. Origins of viral mimicry and its progress in cancer therapy

1.1 The role of endogenous retroviruses

As remnants of ancient retroviral infections, ERVs have long been in equilibrium with the host 29 . Human endogenous retroviruses (HERVs) account for 8% of the human genome and are hardly expressed under normal conditions due to strict epigenetic regulation 30 . HERVs can be classified into 3 prominent families, which are the Class I family: gamma retroviral-like elements, including HERV-T, HERV-I, HERV-H, HERV-W, HERV-R, etc.; the Class II family: β-endotransposon-like elements (HERV-K superfamily); Class Ⅲ family: foamy viral-like elements, including HERV-L, HERV-S, etc. 31 . Previous studies have reported that HERVs play a role in human pathological processes (except cancer) such as type 1 diabetes (T1D) 32 , autoimmune diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SS) are associated with HERVs 33 - 36 . For this review, we will focus on the mechanism of action of HERVs in tumors.

Increasing evidence indicates that the expression of the HERV family shows significant differences in various cancers, highlighting its potential role in tumorigenesis. Studies have shown that HERVs are associated with the development of several types of cancer, including colorectal cancer 37 - 41 , gastric cancer 37 , breast cancer 42 - 53 , prostate cancer 54 - 59 , melanoma 60 - 70 , teratoma 71 - 74 , ovarian cancer 75 , lung cancer 76 , 77 , cervical cancer 78 , 79 , glioblastoma 80 - 82 , pancreatic cancer 83 , 84 , multiple myeloma 85 , kidney cancer 86 - 88 , and bladder cancer 89 (Figure 2 ). For example, research has demonstrated that expression of ERVs correlates with melanoma development 70 , and the use of antiretroviral drugs (doravirine, lamivudine and cabotegravir) inhibits cell viability, invasion and colony-forming ability of melanoma cells, while having no inhibitory effect on normal human epithelial melanocytes 74 . Tumor cells are specific for invasive metastasis, unlimited proliferation, and resistance to death 90 , and a growing number of studies have shown that activation of ERVs correlates with the invasion of tumor cells 91 . Additionally, cancer stem cells (CSCs) are associated with tumorigenesis, invasion and metastasis, and resistance to radiotherapy. It has been suggested that the activation of ERVs may contribute to tumor progression by modulating the functions of CSCs 92 . For example, a study by DO-Ye Kim et al. found that knockdown of the HERV-K env gene significantly inhibited the induction and proliferation of CSCs in the SKOV3 cell line 93 . However, it is worth noting that the role of ERVs may exhibit duality in different biological and therapeutic contexts. Specifically, on the one hand, recent studies have shown that bifunctional inhibitors (J208) of DNA methyltransferases and histone deacetylases by epigenetic means induce ERVs expression, which in turn triggers a viral mimicry response that activates the immune system and exerts an anti-Triple Negative Breast Cancer (TNBC) effect 94 . In addition, Yang et al. found that a dual inhibitor (C02S) of DNA methyltransferases and histone deacetylases, not only upregulated ERVs and activated viral mimicry responses through the MDA5-MAVS signaling pathway in colorectal cancer (CRC) model, but also remodeled the tumor immune microenvironment (TME), enhanced immune cell infiltration, and significantly improved the efficacy of anti-PD-L1 therapy in CRC mouse model. These results suggest that activation of ERVs not only induces immune responses but also enhances the efficacy of immune checkpoint inhibitors (ICIs) 95 . On the other hand, recent studies have shown that ERVs expression is also closely associated with the malignant features of TNBC, and a genome-wide transcriptomic analysis of HERV sequences revealed that TROJAN, a primate long-stranded non-coding RNA, is highly expressed in TNBC and is strongly associated with a poor prognosis by promoting the proliferation and invasion of tumor cells 96 . This phenomenon reflects the complex and diverse roles of ERVs in the tumor microenvironment. Different epigenetic mechanisms, cellular environments, and immune responses may lead to distinct biological effects of ERVs in different contexts. In conclusion, the activation of ERVs and their induced viral mimicry responses have important regulatory roles in cancer development. Although the results suggest that ERVs may serve as biomarkers for cancer and have the potential to become new targets for cancer therapy, further in-depth studies on their mechanisms in different cancer types are needed. The challenge for the future is how to precisely target ERVs to maximize anti-tumor effects while avoiding side effects.

1.2 Potential application of viral mimicry in tumor immunotherapy

Viral mimicry is an endogenous cellular state that affects tumorigenesis and progression by activating normally epigenetically silenced ERVs, further inducing type I/Ⅲ interferon responses. Type I interferons (e.g., IFN-α and IFN-β) promote activating natural killer cells and CD8+ T-cells, augmenting their tumor cell-killing effects. Meanwhile, type Ⅲ interferons (IFN-λ) can modulate immune responses and enhance antitumor immunity in the tumor microenvironment 97 - 99 .

In viral mimicry models, it is more interesting to note that a certain amount of ERV dsRNA is recognized as nonself by pattern recognition receptors to trigger an immune response. However, an adenosine deaminase that acts on RNA (ADAR) prevents MDA5 from sensing endogenous dsRNA as nonself by catalyzing adenosine-to-inosine (A-to-I) editing of dsRNA 100 . In detail, ADAR is a group of enzymes that bind dsRNA to homodimers and catalyze the hydrolytic deamination of adenosine nucleotides to form inosine 101 , 102 . Humans have three ADAR proteins: ADAR1, ADAR2, and ADAR3 103 - 105 . Of these, ADAR1 is universally expressed in almost all tissues and contains both nuclear p110 and interferon-inducible p150 isoforms and expression of ADAR1p150 is thought to be associated with interferon response 106 - 110 . Further studies have shown that interferon-inducible p150 is predominantly found in the nucleus and cytoplasm, that cytoplasmic p150 isoforms specifically regulate MDA5-MAVS-IFN signaling, and that A-to-I editing reduces the ability of MDA5 to carry out its function, making edited dsRNA less efficient at binding to MDA5 111 . In addition, ADARp150 was shown to inhibit another dsRNA sensor, protein kinase R (PKR) 112 , 113 . These RNA sensors are part of the innate immunity against viral infections 114 . Researchers have recently identified ADAR1 as a potential therapeutic target for various cancers. For example, Kyle A and his team proposed in 2021 that ADAR1 is highly expressed in TNBC and that knockdown of ADAR1 attenuates the proliferation of tumor cells 115 ; a report by Kyle A and his team in April 2024 showed that targeting ADAR1 and DHX9 could exert anti-tumor effects by inducing viral mimicry, suggesting that both could serve as effective tools for breast and other cancers 116 . Similarly, Hyeongjwa et al. proposed targeting DEAD-box RNA helicase 3X (DDX3X) and ADAR1 triggers antitumor immunity through dsRNA-mediated endogenous tumor type I interferon response 117 . Therefore, we propose that ADAR1 acts as an interferon-stimulated gene (ISG) that labels dsRNA as itself and inhibits interferon responses, providing negative feedback regulation of viral mimicry responses (Figure 3 ).

The most classic studies on the mechanisms of viral mimicry in cancer therapy are two articles reported in 2015: Roulois et al. proposed that the use of low-dose DNA methyltransferase inhibitors (DNMTis), such as 5-aza-2-deoxycytidine (5-AZA-CdR), could induce a viral mimicry response to target colorectal cancer-initiating cells (CICs), resulting in an anti-tumor effect. However, by disrupting the viral mimicry pathway (e.g., knockdown of MDA5, MAVS, or IRF7) the targeting of CICs by 5-AZA-CdR can be inhibited and its long-term growth effect significantly reduced 118 . Furthermore, Chiappinelli et al. proposed that in ovarian cancer (OC), DNMTis activates the type I interferon response and induces apoptosis by triggering dsRNA perception. Knockdown of the dsRNA sensors TLR3 and MAVS significantly inhibited this immune response, and blockade of IFN-β or its receptor also inhibited the response 16 . These two studies reveal in detail the mechanism of action of viral mimicry in cancer therapy for the first time, validating the direct association between DNMTis, ERVs and anti-tumor immunity. This mechanism provides a new theoretical basis for the combination of epigenetic therapy and tumor immunotherapy, and lays preliminary evidence for future combined treatment strategies. These findings broaden the idea of cancer treatment and provide potential directions for developing new immunotherapies and improving the effectiveness of existing treatments.

In recent studies, RNA deconjugating enzyme DHX9 was found to be a repressor of dsDNA sensing, and further studies have shown that deletion of DHX9 induces activation of the dsRNA sensing pathway and viral mimicry responses and suggested that DHX9 would be a potential target for enhancing antitumor immunity 116 , 119 . In pancreatic cancer, trametinib, as an MEK1/2 inhibitor, induces activation of ERVs and IFN responses, increasing the potential for tumor immunogenicity 120 . Plant homeodomain finger protein 8 (PHF8), a histone lysine demethylase with cancer-restricted antitumor immune function, and in colorectal cancer, deletion of PHF8 activates the antiviral response and significantly improves the therapeutic efficacy of immune checkpoint blockade (ICB) 121 . In addition, studies have also reported that activation of viral mimicry response can increase the sensitivity of tumor cells to radiotherapy. For example, treatment of cervical cancer (CC) with low-dose decitabine (DAC) activated the viral mimicry response, thereby enhancing the sensitivity of CC to chemotherapy 122 . The deletion of histone methyltransferase SETDB1 has been shown to significantly promote the activation of ERVs and induce a type I interferon response, which promotes the sensitivity of cancer cells to radiation therapy 123 . These findings suggest that viral mimicry responses are prevalent in a wide range of cancer types and that their activation not only enhances anti-tumor immune responses, but may also improve tumor sensitivity to radiotherapy and chemotherapy (Table 1 ). Therefore, therapeutic strategies targeting viral mimicry responses are not only expected to enhance the efficacy of cancer immunotherapy, but may also be an important adjuvant therapy to improve the clinical efficacy of existing treatments. These findings provide an important theoretical basis and potential clinical applications for developing new anti-cancer therapeutic strategies in the future.

2. The synergistic interaction between epigenetics and viral mimicry in cancer therapy

2.1 Epigenetic modifications and their integration in cancer therapy: mechanisms and applications of DNA methylation and histone acetylation inhibitors

Epigenetic-targeting drugs have increasingly been used to treat malignant tumors, with common types including DNA methyltransferase inhibitors and histone deacetylase inhibitors 144 . This review focuses on the mechanisms and therapeutic applications of DNA methylation and histone acetylation inhibitors in cancer treatment and further explores the mechanisms of combining epigenetic therapy and viral mimicry against tumors. DNA methylation is the transfer of methyl provided by S adenosine methionine (SAM) to the carbon atom at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMT1, DNMT3A, DNMT3B), ultimately resulting in the formation of 5'methylcytosine 145 . The link between DNA methylation and cancer has been the subject of numerous research personnel. It is one of the most common and well-studied epigenetic modifications in mammals, and DNA methylation analysis has been initially used as a complementary diagnostic tool for various tumors 146 - 148 . Therefore, aberrant DNA methylation is associated with tumorigenesis. Tumors such as colorectal cancer 149 , 150 , breast cancer 151 , 152 , glioblastoma 153 , 154 , hepatocellular carcinoma 155 , 156 , and renal cell carcinoma 157 , 158 have been reported to be associated with DNA methylation abnormalities are associated. In addition, it has been recently reported that the detection of methylation differences in circulating free DNA can be used to sensitively monitor the treatment effect of CRC and detect early pancreatic cancer. As a non-invasive biomarker, it has the advantage of being less cost-effective 159 - 162 .

DNMTis were developed and approved well before the complexity of methylation patterns had been discerned 163 , 164 . Studies have shown that low doses of DNA methyltransferase inhibitors cause inactivation of DNMT1, which in turn causes DNA demethylation 165 . Commonly used DNMTis include azacitidine (AZA) and DAC 166 . These two drugs have remained the mainstay of treatment for elderly AML and MDS patients since their first approval for use to date 167 , 168 . In addition, in some clinical trials, using these two drugs has improved overall survival and quality of life in elderly patients who are not candidates for intense chemotherapy and has also shown that epigenetic therapies are efficacious 169 , 170 . More importantly, it has been reported that DNMTis combined with cytostatic agents promotes apoptosis in CRC cells 171 , 172 ; in both in vivo and ex vivo models, the use of DNMTis significantly inhibited the growth of smooth muscle sarcoma cells 173 ; and in the treatment of breast and ovarian cancers, the combination of PARP inhibitor (PARPi) and DNMTis in combination will restore the sensitivity of breast and ovarian cancer to PARPi treatment 174 ; in a mouse ovarian cancer model, the results showed that DNMTis could activate the type I interferon response, reduce the percentage of macrophages in the tumor microenvironment, and in combination with α-difluoromethylornithine (DFMO) the therapeutic effect was more significant 175 . These results suggest that DNMTis plays an active role in cancer therapy and may improve the therapeutic outcome of a wide range of tumors.

Histones are highly conserved proteins consisting of five types of core proteins, H1, H3, H2A, H2B, and H4, and histone modifications include phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and other modification processes 176 . Histone acetylation is a dynamic modification, and histone acetylation and histone deacetylation work together to maintain normal gene transcription 177 , and the balance between them is tightly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) 178 . Moreover, it was shown that HDAC could be one of the potential targets in cancer therapy 179 . Histone deacetylase inhibitors (HDACis) are new antitumor agents that exert their antitumor effects by regulating gene expression 180 - 182 . In recent years, reports have indicated that the combination of HDACis and DNMTis at low doses significantly improved the antitumor effects in non-small cell lung cancer (NSCLC) 183 and multiple myeloma (MM) 184 , as well as the decrease of cell viability in oral squamous carcinoma (OSCC) after the combination treatment 185 . In addition, in the treatment of breast cancer, HDACis and DNMTis, in combination with conventional chemotherapeutic agents, can exert a positive antitumor mechanism of action by inhibiting the proliferation of breast cancer cells as well as promoting apoptosis 186 , 187 . These results all suggest that targeting epigenetics is an extremely promising cancer treatment.

2.2 Synergistic anti-tumor potential of epigenetic therapies and viral mimicry

As mentioned earlier, DNMTis and HDACis are being extensively investigated as epigenetic regulatory drugs for cancer therapy 17 . These two classes of drugs are currently being used in several clinical trials, alone or in combination with other therapeutic agents, to evaluate their therapeutic effects on a wide range of cancers (Table 2 ). Furthermore, many basic studies have shown that using these two classes of drugs enhances immune signaling, including promoting an interferon response, which induces a viral mimicry response in the body and enhances antitumor effects 188 - 190 . For example, it has been shown that epigenetic inhibitor therapy may trigger the expression of multiple epigenetically silenced genes in gastrointestinal mesenchymal stromal tumor (GIST) cells as well as the activation of the interferon signaling pathway, resulting in antitumor effects 191 . In addition to DNMTis and HDACis, other epigenetic drugs can exert antitumor effects by inducing viral mimicry responses. For example, the zeste enhancer homolog 2 (EZH2) gene, a human homolog of the drosophila zeste gene enhancer, belongs to a key member of the Polycomb group (PcG) family, and possesses histone methylase activity, which catalyzes the methylation of the lysine residue 27 (H3K27) of histone H3 to regulate the expression of oncogenes 192 , 193 . It has been found that EZH2 is highly expressed in a variety of tumors and correlates with tumor prognosis 194 , 195 . Therefore, developing inhibitors targeting EZH2 has become an important research direction in cancer therapy. Recent studies have shown that EZH2 inhibitors (EZH2is) can trigger viral mimicry via RNA and DNA sensing pathways, effectively targeting atypical teratoid rhabdomyosarcomas (ATRTs) 196 . More interestingly, a study found that epigenetic alterations in drug-resistant TNBC, particularly DNA demethylation and modulation of H3K27me3 markers, could evade chemotherapy-induced viral mimicry responses, thereby promoting tumor progression. However, the altered epigenetic state of tumor cells “sensitizes” them to EZH2is after chemoresistance, thereby reversing resistance and restoring the immune system's anti-tumor response 197 . Thus, epigenetic therapies, through multiple mechanisms (e.g., cell cycle regulation and apoptosis induction), can trigger viral mimicry responses and enhance anti-tumor effects, suggesting that epigenetic status modulation may provide new strategies for tumor immunotherapy. These combined effects make the combination of epigenetic therapies and viral mimicry responses a promising strategy for tumor treatment and show broad promise in clinical care.

3. Mechanisms of viral mimicry in the tumor immune response

Several recent studies have reported the impact of viral mimicry phenomena on tumor immunotherapy sensitivity 226 - 228 . These studies have found that viral mimicry can enhance tumor sensitivity to immunotherapy through multiple mechanisms (Figure 4 ). Specifically, viral mimicry has been reported that viral mimicry can promote the immunogenicity of tumor cells, making them easier to recognize and attack by the immune system 94 . Additionally, it can modulate the epigenetic modifications of tumor cells and change their gene expression patterns, thus enhancing the efficacy of immunotherapy 16 , 118 . Furthermore, viral mimicry can improve the therapeutic effect of immune checkpoint blockade (ICB) and promote synergistic inhibition of tumor progression through viral mimicry and tumor immunity 1 , 229 . Collectively, these findings indicate that viral mimicry can potentiate the body's antitumor immune response at multiple levels, providing a strong theoretical and experimental foundation for advancing more effective tumor immunotherapies 230 - 233 .

Recent studies have demonstrated that DAC, as one of the DNMTis, activates viral mimicry responses in renal cell carcinoma. Following DAC treatment, ERVs show increased binding to RIG-I and MDA5, which modulates T-cell activity and induces antitumor immunity 234 . Similarly, treatment with an aurora kinase inhibitor (AURKi) in colorectal cancer has been shown to activate the type I IFN response, which is dependent on MAVS and RIG-I expression 235 . In the treatment of prostate cancer, where metastasis and hormone therapy resistance are major factors in treatment failure, Charles Spruck and his team have proposed a new therapeutic strategy based on viral mimicry. The mechanism of action of this treatment, which is entirely different from traditional treatment, is to target FBXO44 to induce viral mimicry and thus enhance the antitumor immune response, effectively reducing drug resistance. Subsequently, Charles Spruck's team further developed drugs that can induce viral mimicry responses in prostate cancer, which have not yet entered clinical trials due to drug potency and specificity 138 , 139 . These findings suggest an interaction between viral mimicry responses and the tumor immune system, leading to new therapeutic strategies in cancer treatment. This represents a significant step forward in developing next-generation cancer immunotherapies and presents promising prospects for future therapeutic strategies.

4. Potential and challenges of epigenetic and viral mimicry combination immunotherapy

4.1 Potential applications of epigenetic regulation in immunotherapy

At the onset of tumorigenesis, epigenetic abnormalities disrupt critical cellular processes such as the cell cycle, DNA repair, and apoptosis 236 , 237 . Epigenetic therapies have been shown to stimulate antitumor immune responses in both tumor and host cells 238 , 239 . Previous reports have indicated that epigenetic mechanisms have critical regulatory roles in CD4 + T cells 240 , CD8 + T cells 241 , and NK cells 242 . By using immune checkpoint blockade (ICB) and chimeric antigen receptor T cells are the most important therapeutic tools for the tumor immune system 243 . Recent studies have highlighted the potential of novel epigenetic modulators, such as CN133, a novel HDACis, which has been reported to sensitize prostate cancer (PCa) to immunotherapy by remodeling the TME in combination with anti-PD-L1 therapy 244 . Additionally, combination therapies involving DAC, PD-1 blockade, and conventional treatments have demonstrated enhanced tumor cell sensitivity to paclitaxel (PTX) alongside a therapeutic effect on reversing T-cell depletion and improving ICB efficacy in TNBC 245 . Recent reports on PCa have shown that combining HDACi with anti-PD-1 antibody and CTAL-4 antibody can enhance antitumor immunity in ICB-resistant PCa cells 246 . Furthermore, epigenetic abnormalities impact tumor responses to reactive oxygen species (ROS)-based therapies. In colorectal cancer, regulation of ubiquitination and phosphorylation pathways within the epigenome has been identified as a key mechanism in overcoming ROS resistance in the TME, thus enhancing the efficacy of ROS-targeted treatments 247 . Neurogliomas have a low immune response and high drug resistance, which makes them much more challenging to treat. Recent studies have shown that DAC combined with anti-PD-1 immunotherapy can effectively inhibit disease progression and improve antitumor efficacy in neurogliomas 248 . Ovarian cancer is also refractory to treatment, and recent studies have shown that low-dose DAC administration increased NK cell and CD8 + T cell recruitment and prolonged mouse survival in a murine transplantation tumor model of ovarian cancer, while the combination of DAC enhanced the therapeutic efficacy of anti-CTAL-4 treatment, and further studies have found that the combination of DNMTis can enhance the cytotoxic T cell response 249 . These studies suggest that the combination of epigenetic therapy and immunotherapy holds great promise and may become a critical strategy in the future of cancer treatment.

Epigenetic therapy targets abnormal epigenetic markers in cancer cells by modulating epigenetic modifying enzymes, aiming to restore normal cellular function or enhance immune system recognition of tumor cells. This therapeutic strategy differs from traditional radiotherapy, chemotherapy and immunotherapy as it focuses on gene regulatory mechanisms 250 , 251 . Compared to conventional treatments that directly kill cancer cells or prevent their proliferation, epigenetic therapies can maximize the destruction of cancer cells by modulating the epigenetic state of tumor cells, often accompanied by fewer side effects 252 , 253 . Thus, epigenetic drugs show important therapeutic potential as stand-alone therapies or in combination with other treatments 254 . In particular, clinical studies in recent years have highlighted the promise of combining epigenetic drugs with ICIs, especially in tumors that are resistant or refractory to ICIs 255 . For example, a phase II clinical study evaluated the use of the hypomethylating drug Guadecitabine in combination with the anti-PD-1 antibody pembrolizumab in patients with recurrent platinum-resistant ovarian cancer. Of 35 evaluable patients, three experienced partial remission and eight had stable disease, with an overall clinical benefit rate of 31.4%. The median duration of clinical benefit was 6.8 months. Following treatment, patients' peripheral blood mononuclear cells (PBMCs) showed hypomethylation of the Long-interspersed element 1 ( LINE1 ) gene, and tumor biopsies and genomic analyses revealed activation of the tumor immune response. This study demonstrated that epigenetic initiation of combined immune checkpoint inhibitor therapy with hypomethylating agents is feasible and resulted in durable clinical benefit in selected patients with recurrent ovarian cancer 199 . Additionally, in a phase I/Ib study, the combination of pembrolizumab and vorinostat, a histone deacetylase inhibitor, was evaluated in 24 patients with ICI-resistant metastatic NSCLC. The results showed partial remission in one patient and stable disease in eight patients 256 . These findings suggest that the combination of epigenetic drugs and ICIs can effectively overcome drug resistance in conventional immunotherapy, and that combination therapy is promising in the clinic, providing new directions and possibilities for tumor therapy.

4.2 Synergy between epigenetic therapy and immunotherapy: the potential of viral mimicry responses in tumor therapy

Immunotherapy and epigenetic therapy are very promising therapies for treating tumors, and they have great potential and research value in antitumor mechanisms. However, tumor cells have the specificity to evade the immune response 257 , 258 , and more profound research has proposed that tumor cells can also evade immune cells in this way through epigenetic silencing mechanisms 259 . This finding reveals that epigenetic mechanisms can modulate the immune response of tumor cells by inducing viral mimicry, which promotes sensitivity to immunotherapy and improves therapeutic efficacy in tumor patients 183 , 260 . More importantly, Roulois et al. proposed that DNA demethylating agents can activate the interferon response by inducing dsRNA, thereby allowing the organism to mimic viral infection 261 . This study suggests the possibility that epigenetic therapies can improve cancer immunotherapy through viral mimicry responses. This possibility has also been confirmed by recent studies, such as DNMTis in combination with conventional compounds for the treatment of advanced breast cancer, which improves the therapeutic efficacy 262 , and in colorectal cancer, where it has been found that the histone demethylase PHF8 can act as an essential mediator of immune evasion and its absence can stimulate a viral mimicry response. A recent study has shown that using a PHF8-specific small molecule inhibitor iPHF8 can effectively regulate colorectal cancer cell growth and ETC gene transcription 263 , 264 . In ovarian cancer, DNMTis induced a viral mimicry response that triggered a type I interferon response and promoted apoptosis, and a concurrent study found that the combination of CTAL-4 and DAC was more effective against CTAL-4 than when used alone in a melanoma mouse model 16 . In clear renal cell carcinoma (ccRCC), DNMTis, which induces the expression of ERVs and other transposable elements, also enhances T-cell activation, promoting antitumor immune mechanisms of action 234 . In addition, RRx-001, a novel immunomodulatory anticancer agent, can increase immunomodulatory effects directly or indirectly by modulating tumor-associated macrophages and T lymphocytes. The report also indicated that low-dose RRx-001 transient treatment of colorectal cancer cells induced a viral mimicry response, which increased the pharmacological efficacy and therapeutic potential of immunomodulatory RRx-001 131 . These studies suggest that viral mimicry is an intermediate mediator in linking epigenetic therapy and immunotherapy, providing new ideas for developing antitumor drugs and studying antitumor mechanisms 228 , 265 .

5. Conclusions and future perspectives

Viral mimicry therapy, epigenetic therapy and tumor immunotherapy complement each other to build a comprehensive treatment strategy, which brings new therapeutic prospects for cancer patients. Viral mimicry activates the immune system, epigenetic therapy enhances the therapeutic effect, and tumor immunotherapy improves the body's immune response. Combining the three can effectively inhibit tumor growth and metastasis, which is one of the critical directions for future cancer treatment. However, at the same time, it also faces many challenges, such as the selection of suitable inducers in viral mimicry therapy and in-depth study of the therapeutic mechanism, the regulation of epigenetic drug dosage and the development of new drugs, as well as how to effectively circumvent the adverse events that may be induced by immunotherapy. Furthermore, while epigenetic therapy and immunotherapy both show great potential, their safety and tolerability profiles need further exploration in large-scale trials, particularly regarding the cumulative toxicities from prolonged use. Additionally, the inherent heterogeneity of tumors complicates the treatment's effectiveness, as not all tumor cells may respond equally to the three therapies. Identifying biomarkers for selecting patients most likely to benefit from this integrated strategy will be crucial for improving outcomes. More importantly, the interactions between viral mimetic therapy, epigenetic therapy, and tumor immunotherapy have not been fully elucidated, and further research is needed to reveal the links between them. The synergistic effect of these therapies is essential to improve the clinical outcome of cancer patients. Therefore, more basic research and clinical trials are needed to refine these therapeutic strategies to provide more effective treatment options for most cancer patients and maximize their survival and quality of life.

We want to express our gratitude for the drawing materials provided by BioRender.

Funding

This work was supported by the Hunan Natural Science Foundation Outstanding Youth Fund [2023JJ10091], the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University [BJ202203], the Beijing Natural Science Foundation [L244031], the National Natural Science Foundation of China [82302625].

Author contributions

C.W., L.W., D.X. and W.R. designed the review, D.X., W.R., and L.J. undertook the literature research, manuscript writing, and drafting, C.W. and L.W. further checked and revised the manuscript. W.R., Z.X.J and L.J.Z. participated in the revision. All authors have read and corrected the article.

Abbreviations

endogenous retroviruses

human endogenous retroviruses

double-stranded RNAs

pattern recognition receptors

melanoma differentiation-associated gene 5

mitochondrial antiviral signaling

TANK binding kinase 1

interferon regulatory factor 7

DNA methyltransferase

DNA methyltransferase inhibitors

azacitidine

decitabine

histone deacetylase

Histone deacetylase inhibitors

adenosine deaminase that acts on RNA

interferon-stimulated gene

5-aza-2-deoxycytidine

EZH2 inhibitors

immune checkpoint blockade

immune checkpoint inhibitors

tumor microenvironment

1 Micevic G Bosenberg MW Yan Q The Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy Clin Cancer Res 2023 29 1173 82 36449280 10.1158/1078-0432.CCR-22-0784 PMC10073242

2 Lindholm HT Chen R De Carvalho DD Endogenous retroelements as alarms for disruptions to cellular homeostasis Trends Cancer 2023 9 55 68 36216729 10.1016/j.trecan.2022.09.001

3 Petrizzo A Ragone C Cavalluzzo B Mauriello A Manolio C Tagliamonte M Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy Cancers (Basel) 2021 13 1999 33919186 10.3390/cancers13091999 PMC8122352

4 Jansz N Faulkner GJ Endogenous retroviruses in the origins and treatment of cancer Genome Biol 2021 22 147 33971937 10.1186/s13059-021-02357-4 PMC8108463

5 Jiang Y Zhang H Wang J Chen J Guo Z Liu Y Exploiting RIG-I-like receptor pathway for cancer immunotherapy J Hematol Oncol 2023 16 8 36755342 10.1186/s13045-023-01405-9 PMC9906624

6 Perry AK Chen G Zheng D Tang H Cheng G The host type I interferon response to viral and bacterial infections Cell Res 2005 15 407 22 15987599 10.1038/sj.cr.7290309

7 Yu T Yi YS Yang Y Oh J Jeong D Cho JY The pivotal role of TBK1 in inflammatory responses mediated by macrophages Mediators Inflamm 2012 2012 979105 23304064 10.1155/2012/979105 PMC3523167

8 Cui J Chen Y Wang HY Wang RF Mechanisms and pathways of innate immune activation and regulation in health and cancer Hum Vaccin Immunother 2014 10 3270 85 25625930 10.4161/21645515.2014.979640 PMC4514086

9 Hu YW Zhang J Wu XM Cao L Nie P Chang MX TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation Front Immunol 2018 9 84 29441066 10.3389/fimmu.2018.00084 PMC5797597

10 Flavahan WA Gaskell E Bernstein BE Epigenetic plasticity and the hallmarks of cancer Science 2017 357 eaal2380 28729483 10.1126/science.aal2380 PMC5940341

11 Feinberg AP Koldobskiy MA Göndör A Epigenetic modulators, modifiers and mediators in cancer aetiology and progression Nat Rev Genet 2016 17 284 99 26972587 10.1038/nrg.2016.13 PMC4888057

12 Baylin SB Jones PA Epigenetic Determinants of Cancer Cold Spring Harb Perspect Biol 2016 8 a019505 27194046 10.1101/cshperspect.a019505 PMC5008069

13 Ge T Gu X Jia R Ge S Chai P Zhuang A Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities Cancer Commun (Lond) 2022 42 1049 82 36266736 10.1002/cac2.12374 PMC9648395

14 Biswas S Rao CM Epigenetics in cancer: Fundamentals and Beyond Pharmacol Ther 2017 173 118 34 28188812 10.1016/j.pharmthera.2017.02.011

15 Janin M Esteller M Epigenetic Awakening of Viral Mimicry in Cancer Cancer Discov 2020 10 1258 60 32873618 10.1158/2159-8290.CD-20-0947

16 Chiappinelli KB Strissel PL Desrichard A Li H Henke C Akman B Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses Cell 2015 162 974 86 26317466 10.1016/j.cell.2015.07.011 PMC4556003

17 Daskalakis M Brocks D Sheng YH Islam MS Ressnerova A Assenov Y Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors Cell Cycle 2018 17 811 22 29633898 10.1080/15384101.2018.1442623 PMC6056222

18 Benmelech S Le T McKay M Nam J Subramaniam K Tellez D Biophysical and biochemical aspects of immune cell-tumor microenvironment interactions APL Bioeng 2024 8 021502 38572312 10.1063/5.0195244 PMC10990568

19 Guo Q Qian ZM Macrophage based drug delivery: Key challenges and strategies Bioact Mater 2024 38 55 72 38699242 10.1016/j.bioactmat.2024.04.004 PMC11061709

20 Oliveira G Wu CJ Dynamics and specificities of T cells in cancer immunotherapy Nat Rev Cancer 2023 23 295 316 37046001 10.1038/s41568-023-00560-y PMC10773171

21 Yu Q Ding J Li S Li Y Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions Cancer Lett 2024 590 216856 38583651 10.1016/j.canlet.2024.216856

22 Alizadeh D Larmonier N Chemotherapeutic targeting of cancer-induced immunosuppressive cells Cancer Res 2014 74 2663 8 24778417 10.1158/0008-5472.CAN-14-0301 PMC4041515

23 Demaria O Cornen S Daëron M Morel Y Medzhitov R Vivier E Harnessing innate immunity in cancer therapy Nature 2019 574 45 56 31578484 10.1038/s41586-019-1593-5

24 Evdokimova V Gassmann H Radvanyi L Burdach SEG Current State of Immunotherapy and Mechanisms of Immune Evasion in Ewing Sarcoma and Osteosarcoma Cancers (Basel) 2022 15 272 36612267 10.3390/cancers15010272 PMC9818129

25 Karbach J Neumann A Brand K Wahle C Siegel E Maeurer M Phase I clinical trial of mixed bacterial vaccine (Coley's toxins) in patients with NY-ESO-1 expressing cancers: immunological effects and clinical activity Clin Cancer Res 2012 18 5449 59 22847809 10.1158/1078-0432.CCR-12-1116

26 Rui R Zhou L He S Cancer immunotherapies: advances and bottlenecks Front Immunol 2023 14 1212476 37691932 10.3389/fimmu.2023.1212476 PMC10484345

27 Zhong F Lin Y Zhao L Yang C Ye Y Shen Z Reshaping the tumour immune microenvironment in solid tumours via tumour cell and immune cell DNA methylation: from mechanisms to therapeutics Br J Cancer 2023 129 24 37 37117649 10.1038/s41416-023-02292-0 PMC10307880

28 Wolff F Leisch M Greil R Risch A Pleyer L The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation Cell Commun Signal 2017 15 13 28359286 10.1186/s12964-017-0168-z PMC5374693

29 Heij HA Obertop H van Blankenstein M ten Kate FW Westbroek DL Relationship between functional and histological changes in chronic pancreatitis Dig Dis Sci 1986 31 1009 13 3757716 10.1007/BF01300251

30 Fang Y Zhang MC He Y Li C Fang H Xu PP Human endogenous retroviruses as epigenetic therapeutic targets in TP53-mutated diffuse large B-cell lymphoma Signal Transduct Target Ther 2023 8 381 37798292 10.1038/s41392-023-01626-x PMC10556001

31 Suntsova M Garazha A Ivanova A Kaminsky D Zhavoronkov A Buzdin A Molecular functions of human endogenous retroviruses in health and disease Cell Mol Life Sci 2015 72 3653 75 26082181 10.1007/s00018-015-1947-6 PMC11113533

32 Levet S Medina J Joanou J Demolder A Queruel N Réant K An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes JCI Insight 2017 2 e94387 28878130 10.1172/jci.insight.94387 PMC5621895

33 Halcrow PW Quansah DNK Kumar N Steiner JP Nath A Geiger JD HERV-K (HML-2) Envelope Protein Induces Mitochondrial Depolarization and Neurotoxicity via Endolysosome Iron Dyshomostasis J Neurosci 2024 44 e0826232024 38383499 10.1523/JNEUROSCI.0826-23.2024 PMC10993035

34 Talal N Flescher E Dang H Are endogenous retroviruses involved in human autoimmune disease? J Autoimmun 1992 5 Suppl A: 61-6 10.1016/0896-8411(92)90020-q 1323968

35 Herrmann M Hagenhofer M Kalden JR Retroviruses and systemic lupus erythematosus Immunol Rev 1996 152 145 56 8930671 10.1111/j.1600-065x.1996.tb00914.x

36 Nakagawa K Harrison LC The potential roles of endogenous retroviruses in autoimmunity Immunol Rev 1996 152 193 236 8930674 10.1111/j.1600-065x.1996.tb00917.x

37 Tavakolian S Iranshahi M Faghihloo E The Evaluation of HERV-K np9, rec, gag Expression in Isolated Human Peripheral Blood Mononuclear Cell (PBMC) of Gastric and Colon Cancer Adv Biomed Res 2023 12 131 37434925 10.4103/abr.abr_288_22 PMC10331531

38 Peng B Reeves KKL Lee SWY Chung THY Hui HWL Leung AHL Physical, psychological, and behavioral problems among children and adolescents in countries with different economic statuses during the COVID-19 pandemic: a systematic review and meta-analysis Front Pediatr 2023 11 1181186 37342536 10.3389/fped.2023.1181186 PMC10277820

39 Ko EJ Ock MS Choi YH Iovanna JL Mun S Han K Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells Int J Mol Sci 2021 22 3941 33920455 10.3390/ijms22083941 PMC8070087

40 Dolci M Favero C Toumi W Favi E Tarantini L Signorini L Human Endogenous Retroviruses Long Terminal Repeat Methylation, Transcription, and Protein Expression in Human Colon Cancer Front Oncol 2020 10 569015 33194657 10.3389/fonc.2020.569015 PMC7653092

41 Liang Q Xu Z Xu R Wu L Zheng S Expression patterns of non-coding spliced transcripts from human endogenous retrovirus HERV-H elements in colon cancer PLoS One 2012 7 e29950 22238681 10.1371/journal.pone.0029950 PMC3253121

42 Zhou F Li M Wei Y Lin K Lu Y Shen J Activation of HERV-K Env protein is essential for tumorigenesis and metastasis of breast cancer cells Oncotarget 2016 7 84093 117 27557521 10.18632/oncotarget.11455 PMC5356647

43 Wei Y Wei H Wei Y Tan A Chen X Liao X Screening and Identification of Human Endogenous Retrovirus-K mRNAs for Breast Cancer Through Integrative Analysis of Multiple Datasets Front Oncol 2022 12 820883 35265522 10.3389/fonc.2022.820883 PMC8900282

44 Wang-Johanning F Frost AR Jian B Epp L Lu DW Johanning GL Quantitation of HERV-K env gene expression and splicing in human breast cancer Oncogene 2003 22 1528 35 12629516 10.1038/sj.onc.1206241

45 Zhou F Krishnamurthy J Wei Y Li M Hunt K Johanning GL Chimeric antigen receptor T cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras Oncoimmunology 2015 4 e1047582 26451325 10.1080/2162402X.2015.1047582 PMC4589998

46 Tavakolian S Goudarzi H Faghihloo E Evaluating the expression level of HERV-K env, np9, rec and gag in breast tissue Infect Agent Cancer 2019 14 42 31798679 10.1186/s13027-019-0260-7 PMC6884765

47 Golan M Hizi A Resau JH Yaal-Hahoshen N Reichman H Keydar I Human endogenous retrovirus (HERV-K) reverse transcriptase as a breast cancer prognostic marker Neoplasia 2008 10 521 33 18516289 10.1593/neo.07986 PMC2386537

48 Rinkoff S Letter to the editor: How well is the NHS set up for issues surrounding gender identity? Int J Surg 2019 68 91 31265916 10.1016/j.ijsu.2019.06.021

49 Wang-Johanning F Li M Esteva FJ Hess KR Yin B Rycaj K Human endogenous retrovirus type K antibodies and mRNA as serum biomarkers of early-stage breast cancer Int J Cancer 2014 134 587 95 23873154 10.1002/ijc.28389 PMC4191919

50 Wang-Johanning F Radvanyi L Rycaj K Plummer JB Yan P Sastry KJ Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients Cancer Res 2008 68 5869 77 18632641 10.1158/0008-5472.CAN-07-6838 PMC5802396

51 Wang-Johanning F Frost AR Johanning GL Khazaeli MB LoBuglio AF Shaw DR Expression of human endogenous retrovirus k envelope transcripts in human breast cancer Clin Cancer Res 2001 7 1553 60 11410490

52 Rhyu DW Kang YJ Ock MS Eo JW Choi YH Kim WJ Expression of human endogenous retrovirus env genes in the blood of breast cancer patients Int J Mol Sci 2014 15 9173 83 24964007 10.3390/ijms15069173 PMC4100088

53 Lemaître C Tsang J Bireau C Heidmann T Dewannieux M A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion PLoS Pathog 2017 13 e1006451 28651004 10.1371/journal.ppat.1006451 PMC5501692

54 Manca MA Solinas T Simula ER Noli M Ruberto S Madonia M HERV-K and HERV-H Env Proteins Induce a Humoral Response in Prostate Cancer Patients Pathogens 2022 11 95 35056043 10.3390/pathogens11010095 PMC8778306

55 Rezaei SD Hayward JA Norden S Pedersen J Mills J Hearps AC HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer Viruses 2021 13 449 33802118 10.3390/v13030449 PMC7999808

56 Wallace TA Downey RF Seufert CJ Schetter A Dorsey TH Johnson CA Elevated HERV-K mRNA expression in PBMC is associated with a prostate cancer diagnosis particularly in older men and smokers Carcinogenesis 2014 35 2074 83 24858205 10.1093/carcin/bgu114 PMC4146419

57 Schulz WA Does HERV-K represent a potential therapeutic target for prostate cancer? Expert Opin Ther Targets 2017 21 921 4 28847189 10.1080/14728222.2017.1373095

58 Agoni L Guha C Lenz J Detection of Human Endogenous Retrovirus K (HERV-K) Transcripts in Human Prostate Cancer Cell Lines Front Oncol 2013 3 180 23847768 10.3389/fonc.2013.00180 PMC3705622

59 Reis BS Jungbluth AA Frosina D Holz M Ritter E Nakayama E Prostate cancer progression correlates with increased humoral immune response to a human endogenous retrovirus GAG protein Clin Cancer Res 2013 19 6112 25 24081977 10.1158/1078-0432.CCR-12-3580

60 Cardelli M Doorn RV Larcher L Donato MD Piacenza F Pierpaoli E Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients Epigenomics 2020 12 1689 706 33125285 10.2217/epi-2020-0127

61 Argaw-Denboba A Balestrieri E Serafino A Cipriani C Bucci I Sorrentino R HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features J Exp Clin Cancer Res 2017 36 20 28125999 10.1186/s13046-016-0485-x PMC5270369

62 Krishnamurthy J Rabinovich BA Mi T Switzer KC Olivares S Maiti SN Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma Clin Cancer Res 2015 21 3241 51 25829402 10.1158/1078-0432.CCR-14-3197 PMC4506228

63 Schmitt K Reichrath J Roesch A Meese E Mayer J Transcriptional profiling of human endogenous retrovirus group HERV-K(HML-2) loci in melanoma Genome Biol Evol 2013 5 307 28 23338945 10.1093/gbe/evt010 PMC3590776

64 Büscher K Trefzer U Hofmann M Sterry W Kurth R Denner J Expression of human endogenous retrovirus K in melanomas and melanoma cell lines Cancer Res 2005 65 4172 80 15899808 10.1158/0008-5472.CAN-04-2983

65 Serafino A Balestrieri E Pierimarchi P Matteucci C Moroni G Oricchio E The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation Exp Cell Res 2009 315 849 62 19167380 10.1016/j.yexcr.2008.12.023

66 Singh M Cai H Bunse M Feschotte C Izsvák Z Human Endogenous Retrovirus K Rec forms a Regulatory Loop with MITF that Opposes the Progression of Melanoma to an Invasive Stage Viruses 2020 12 1303 33202765 10.3390/v12111303 PMC7696977

67 Singh S Kaye S Francis N Peston D Gore M McClure M Human endogenous retrovirus K (HERV-K) rec mRNA is expressed in primary melanoma but not in benign naevi or normal skin Pigment Cell Melanoma Res 2013 26 426 8 23311654 10.1111/pcmr.12066

68 Schiavetti F Thonnard J Colau D Boon T Coulie PG A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes Cancer Res 2002 62 5510 6 12359761

69 Schanab O Humer J Gleiss A Mikula M Sturlan S Grunt S Expression of human endogenous retrovirus K is stimulated by ultraviolet radiation in melanoma Pigment Cell Melanoma Res 2011 24 656 65 21501418 10.1111/j.1755-148X.2011.00860.x

70 Muster T Waltenberger A Grassauer A Hirschl S Caucig P Romirer I An endogenous retrovirus derived from human melanoma cells Cancer Res 2003 63 8735 41 14695188

71 Chan SM Sapir T Park SS Rual JF Contreras-Galindo R Reiner O The HERV-K accessory protein Np9 controls viability and migration of teratocarcinoma cells PLoS One 2019 14 e0212970 30818388 10.1371/journal.pone.0212970 PMC6394991

72 Morozov VA Morozov AV A Comprehensive Analysis of Human Endogenous Retroviruses HERV-K (HML.2) from Teratocarcinoma Cell Lines and Detection of Viral Cargo in Microvesicles Int J Mol Sci 2021 22 12398 34830279 10.3390/ijms222212398 PMC8619701

73 Götzinger N Sauter M Roemer K Mueller-Lantzsch N Regulation of human endogenous retrovirus-K Gag expression in teratocarcinoma cell lines and human tumours J Gen Virol 1996 77 Pt 12 2983 90 9000088 10.1099/0022-1317-77-12-2983

74 Zanrè V Bellinato F Cardile A Passarini C Monticelli J Di Bella S Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines Int J Mol Sci 2024 25 1615 38338893 10.3390/ijms25031615 PMC10855363

75 Iramaneerat K Rattanatunyong P Khemapech N Triratanachat S Mutirangura A HERV-K hypomethylation in ovarian clear cell carcinoma is associated with a poor prognosis and platinum resistance Int J Gynecol Cancer 2011 21 51 7 21330831 10.1097/IGC.0b013e3182021c1a

76 Yang C Guo X Li J Han J Jia L Wen HL Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells Front Microbiol 2022 13 850444 35359739 10.3389/fmicb.2022.850444 PMC8960717

77 Zare M Mostafaei S Ahmadi A Azimzadeh Jamalkandi S Abedini A Esfahani-Monfared Z Human endogenous retrovirus env genes: Potential blood biomarkers in lung cancer Microb Pathog 2018 115 189 93 29274460 10.1016/j.micpath.2017.12.040

78 Curty G Menezes AN Brant AC de Mulder Rougvie M Moreira MÂ M Soares MA Expression of Retroelements in Cervical Cancer and Their Interplay with HPV Infection and Host Gene Expression Cancers (Basel) 2021 13 3513 34298727 10.3390/cancers13143513 PMC8306386

79 Soleimani-Jelodar R Arashkia A Shoja Z Akhavan S Yarandi F Sharifian K The expression analysis of human endogenous retrovirus-K Env, Np9, and Rec transcripts in cervical cancer J Med Virol 2024 96 e29501 38445563 10.1002/jmv.29501

80 Shah AH Rivas SR Doucet-O'Hare TT Govindarajan V DeMarino C Wang T Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma J Clin Invest 2023 133 e167929 37395282 10.1172/JCI167929 PMC10313366

81 Shah AH Govindarajan V Doucet-O'Hare TT Rivas S Ampie L DeMarino C Differential expression of an endogenous retroviral element [HERV-K(HML-6)] is associated with reduced survival in glioblastoma patients Sci Rep 2022 12 6902 35477752 10.1038/s41598-022-10914-5 PMC9046263

82 Hothi P Cobbs C The potential role of human endogenous retrovirus K in glioblastoma J Clin Invest 2023 133 e170885 37395278 10.1172/JCI170885 PMC10313359

83 Li M Radvanyi L Yin B Rycaj K Li J Chivukula R Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth Clin Cancer Res 2017 23 5892 911 28679769 10.1158/1078-0432.CCR-17-0001 PMC5777511

84 Li M Radvanyi L Yin B Rycaj K Li J Chivukula R Correction: Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth Clin Cancer Res 2019 25 2936 31043384 10.1158/1078-0432.CCR-19-0700

85 Masuda Y Ishihara R Murakami Y Watanabe S Asao Y Gotoh N Clinical significance of human endogenous retrovirus K (HERV-K) in multiple myeloma progression Int J Hematol 2023 117 563 77 36522589 10.1007/s12185-022-03513-7

86 Cherkasova E Scrivani C Doh S Weisman Q Takahashi Y Harashima N Detection of an Immunogenic HERV-E Envelope with Selective Expression in Clear Cell Kidney Cancer Cancer Res 2016 76 2177 85 26862115 10.1158/0008-5472.CAN-15-3139 PMC4873424

87 Takahashi Y Harashima N Kajigaya S Yokoyama H Cherkasova E McCoy JP Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells J Clin Invest 2008 118 1099 109 18292810 10.1172/JCI34409 PMC2248804

88 Cherkasova E Malinzak E Rao S Takahashi Y Senchenko VN Kudryavtseva AV Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer Oncogene 2011 30 4697 706 21602888 10.1038/onc.2011.179 PMC3161150

89 Park EG Lee DH Kim WR Lee YJ Bae WH Kim JM Human Endogenous Retrovirus-H-Derived miR-4454 Inhibits the Expression of DNAJB4 and SASH1 in Non-Muscle-Invasive Bladder Cancer Genes (Basel) 2023 14 1410 37510314 10.3390/genes14071410 PMC10379226

90 Hanahan D Weinberg RA Hallmarks of cancer: the next generation Cell 2011 144 646 74 21376230 10.1016/j.cell.2011.02.013

91 Cherkasova EA Chen L Childs RW Mechanistic regulation of HERV activation in tumors and implications for translational research in oncology Front Cell Infect Microbiol 2024 14 1358470 38379771 10.3389/fcimb.2024.1358470 PMC10877039

92 Matteucci C Balestrieri E Argaw-Denboba A Sinibaldi-Vallebona P Human endogenous retroviruses role in cancer cell stemness Semin Cancer Biol 2018 53 17 30 30317035 10.1016/j.semcancer.2018.10.001

93 Kim DY Kim H Ko EJ Koh SB Kim H Lee JY Correlation analysis of cancer stem cell marker CD133 and human endogenous retrovirus (HERV)-K env in SKOV3 ovarian cancer cells Genes Genomics 2024 46 511 8 38457096 10.1007/s13258-024-01499-6

94 Fan W Li W Li L Qin M Mao C Yuan Z Bifunctional HDAC and DNMT inhibitor induces viral mimicry activates the innate immune response in triple-negative breast cancer Eur J Pharm Sci 2024 197 106767 38636781 10.1016/j.ejps.2024.106767

95 Yang Z Chu B Tu Y Li L Chen D Huang S Dual inhibitors of DNMT and HDAC remodels the immune microenvironment of colorectal cancer and enhances the efficacy of anti-PD-L1 therapy Pharmacol Res 2024 206 107271 38906202 10.1016/j.phrs.2024.107271

96 Jin X Xu XE Jiang YZ Liu YR Sun W Guo YJ The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation Sci Adv 2019 5 eaat9820 30854423 10.1126/sciadv.aat9820 PMC6402854

97 Parker BS Rautela J Hertzog PJ Antitumour actions of interferons: implications for cancer therapy Nat Rev Cancer 2016 16 131 44 26911188 10.1038/nrc.2016.14

98 Kelly JM Darcy PK Markby JL Godfrey DI Takeda K Yagita H Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection Nat Immunol 2002 3 83 90 11743585 10.1038/ni746

99 Kotenko SV Gallagher G Baurin VV Lewis-Antes A Shen M Shah NK IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex Nat Immunol 2003 4 69 77 12483210 10.1038/ni875

100 Liddicoat BJ Piskol R Chalk AM Ramaswami G Higuchi M Hartner JC RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself Science 2015 349 1115 20 26275108 10.1126/science.aac7049 PMC5444807

101 Bazak L Haviv A Barak M Jacob-Hirsch J Deng P Zhang R A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes Genome Res 2014 24 365 76 24347612 10.1101/gr.164749.113 PMC3941102

102 Wagner RW Smith JE Cooperman BS Nishikura K A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs Proc Natl Acad Sci U S A 1989 86 2647 51 2704740 10.1073/pnas.86.8.2647 PMC286974

103 Kim U Wang Y Sanford T Zeng Y Nishikura K Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing Proc Natl Acad Sci U S A 1994 91 11457 61 7972084 10.1073/pnas.91.24.11457 PMC45250

104 Melcher T Maas S Herb A Sprengel R Seeburg PH Higuchi M A mammalian RNA editing enzyme Nature 1996 379 460 4 8559253 10.1038/379460a0

105 Chen CX Cho DS Wang Q Lai F Carter KC Nishikura K A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains Rna 2000 6 755 67 10836796 10.1017/s1355838200000170 PMC1369955

106 George CX Samuel CE Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible Proc Natl Acad Sci U S A 1999 96 4621 6 10200312 10.1073/pnas.96.8.4621 PMC16382

107 Desterro JM Keegan LP Lafarga M Berciano MT O'Connell M Carmo-Fonseca M Dynamic association of RNA-editing enzymes with the nucleolus J Cell Sci 2003 116 1805 18 12665561 10.1242/jcs.00371

108 Patterson JB Samuel CE Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase Mol Cell Biol 1995 15 5376 88 7565688 10.1128/mcb.15.10.5376 PMC230787

109 Shiromoto Y Sakurai M Minakuchi M Ariyoshi K Nishikura K ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells Nat Commun 2021 12 1654 33712600 10.1038/s41467-021-21921-x PMC7955049

110 Baker AR Slack FJ ADAR1 and its implications in cancer development and treatment Trends Genet 2022 38 821 30 35459560 10.1016/j.tig.2022.03.013 PMC9283316

111 Pestal K Funk CC Snyder JM Price ND Treuting PM Stetson DB Isoforms of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development Immunity 2015 43 933 44 26588779 10.1016/j.immuni.2015.11.001 PMC4654992

112 Koval L Kalashnyk O Lykhmus O Skok M α7 nicotinic acetylcholine receptors are involved in suppression of the antibody immune response J Neuroimmunol 2018 318 8 14 29395323 10.1016/j.jneuroim.2018.01.012

113 Song B Shiromoto Y Minakuchi M Nishikura K The role of RNA editing enzyme ADAR1 in human disease Wiley Interdiscip Rev RNA 2022 13 e1665 34105255 10.1002/wrna.1665 PMC8651834

114 Paget M Cadena C Ahmad S Wang HT Jordan TX Kim E Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA Mol Cell 2023 83 1180 96.e8 37028415 10.1016/j.molcel.2023.03.010 PMC10170497

115 Kung CP Cottrell KA Ryu S Bramel ER Kladney RD Bao EA Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer Oncogene 2021 40 189 202 33110236 10.1038/s41388-020-01515-5 PMC7796950

116 Cottrell KA Ryu S Pierce JR Soto Torres L Bohlin HE Schab AM Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells Cancer Res Commun 2024 4 986 1003 38530197 10.1158/2767-9764.CRC-23-0488 PMC10993856

117 Choi H Kwon J Cho MS Sun Y Zheng X Wang J Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response Cancer Res 2021 81 3607 20 33941613 10.1158/0008-5472.CAN-20-3790 PMC8597981

118 Roulois D Loo Yau H Singhania R Wang Y Danesh A Shen SY DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts Cell 2015 162 961 73 26317465 10.1016/j.cell.2015.07.056 PMC4843502

119 Chiappinelli KB Targeting the DHX9 RNA Helicase to Induce Antitumor Immunity in Small-Cell Lung Cancer Cancer Discov 2024 14 389 91 38426559 10.1158/2159-8290.CD-23-1523

120 Cortesi A Gandolfi F Arco F Di Chiaro P Valli E Polletti S Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer Sci Adv 2024 10 eadk5386 38536927 10.1126/sciadv.adk5386 PMC10971493

121 Liu Y Hu L Wu Z Yuan K Hong G Lian Z Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons Nat Commun 2023 14 4225 37454216 10.1038/s41467-023-39943-y PMC10349869

122 Alexandraki A Strati K Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy Int J Mol Sci 2022 23 14042 36430521 10.3390/ijms232214042 PMC9692951

123 Pan D Bao X Hu M Jiao M Li F Li CY SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy Cancer Res 2022 82 2748 60 35648422 10.1158/0008-5472.CAN-21-3523 PMC9357127

124 Huang W Zhu Q Shi Z Tu Y Li Q Zheng W Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer Cell Death Discov 2024 10 143 38490978 10.1038/s41420-024-01895-7 PMC10943227

125 Zhang S Liu X Chen W Zhang K Wu Q Wei Y Targeting TAF1 with BAY-299 induces antitumor immunity in triple-negative breast cancer Biochem Biophys Res Commun 2023 665 55 63 37148745 10.1016/j.bbrc.2023.04.100

126 Wu Q Nie DY Ba-Alawi W Ji Y Zhang Z Cruickshank J PRMT inhibition induces a viral mimicry response in triple-negative breast cancer Nat Chem Biol 2022 18 821 30 35578032 10.1038/s41589-022-01024-4 PMC9337992

127 Bowling EA Wang JH Gong F Wu W Neill NJ Kim IS Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer Cell 2021 184 384 403.e21 33450205 10.1016/j.cell.2020.12.031 PMC8635244

128 Bolis M Paroni G Fratelli M Vallerga A Guarrera L Zanetti A All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells Cancers (Basel) 2020 12 1169 32384653 10.3390/cancers12051169 PMC7281473

129 Goel S DeCristo MJ Watt AC BrinJones H Sceneay J Li BB CDK4/6 inhibition triggers anti-tumour immunity Nature 2017 548 471 5 28813415 10.1038/nature23465 PMC5570667

130 Chomiak AA Tiedemann RL Liu Y Kong X Cui Y Wiseman AK Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling Sci Adv 2024 10 eadk4423 38536911 10.1126/sciadv.adk4423 PMC10971413

131 Zhao H Ning S Nolley R Scicinski J Oronsky B Knox SJ The immunomodulatory anticancer agent, RRx-001, induces an interferon response through epigenetic induction of viral mimicry Clin Epigenetics 2017 9 4 28149332 10.1186/s13148-017-0312-z PMC5270305

132 Murayama T Nakayama J Jiang X Miyata K Morris AD Cai KQ Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer Cancer Discov 2024 14 468 91 38189443 10.1158/2159-8290.CD-23-0486 PMC10905673

133 Nikolic A Maule F Bobyn A Ellestad K Paik S Marhon SA macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma Nat Commun 2023 14 3062 37244935 10.1038/s41467-023-38919-2 PMC10224928

134 Ramsoomair CK Ceccarelli M Heiss JD Shah AH The epitranscriptome of high-grade gliomas: a promising therapeutic target with implications from the tumor microenvironment to endogenous retroviruses J Transl Med 2023 21 893 38071304 10.1186/s12967-023-04725-z PMC10709919

135 Chan FF Yuen VW Shen J Chin DW Law CT Wong BP Inhibition of CAF-1 histone chaperone complex triggers cytosolic DNA and dsRNA sensing pathways and induces intrinsic immunity of hepatocellular carcinoma Hepatology 2024 80 295 311 38051950 10.1097/HEP.0000000000000709

136 Yalala S Gondane A Poulose N Liang J Mills IG Itkonen HM CDK9 inhibition activates innate immune response through viral mimicry Faseb j 2024 38 e23628 38661032 10.1096/fj.202302375R

137 Alizadeh-Ghodsi M Owen KL Townley SL Zanker D Rollin SPG Hanson AR Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer Cancer Res Commun 2022 2 706 24 36923279 10.1158/2767-9764.CRC-21-0139 PMC10010308

138 Shen JZ Spruck C Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry Cell Stress 2021 5 37 9 33681705 10.15698/cst2021.03.245 PMC7921849

139 Shen JZ Qiu Z Wu Q Finlay D Garcia G Sun D FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells Cell 2021 184 352 69.e23 33357448 10.1016/j.cell.2020.11.042 PMC8043252

140 Cao W Kang R Xiang Y Hong J Human Endogenous Retroviruses in Clear Cell Renal Cell Carcinoma: Biological Functions and Clinical Values Onco Targets Ther 2020 13 7877 85 32821127 10.2147/OTT.S259534 PMC7423347

141 Li HT Jang HJ Rohena-Rivera K Liu M Gujar H Kulchycki J RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer Cell Rep 2023 42 112016 36662621 10.1016/j.celrep.2023.112016 PMC10034851

142 Di Marco T Bianchi F Sfondrini L Todoerti K Bongarzone I Maffioli EM COPZ1 depletion in thyroid tumor cells triggers type I IFN response and immunogenic cell death Cancer Lett 2020 476 106 19 32061953 10.1016/j.canlet.2020.02.011

143 Liu M Thomas SL DeWitt AK Zhou W Madaj ZB Ohtani H Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells Cancer Res 2018 78 5754 66 30185548 10.1158/0008-5472.CAN-17-3953 PMC6191339

144 Bates SE Epigenetic Therapies for Cancer N Engl J Med 2020 383 650 63 32786190 10.1056/NEJMra1805035

145 Nishiyama A Nakanishi M Navigating the DNA methylation landscape of cancer Trends Genet 2021 37 1012 27 34120771 10.1016/j.tig.2021.05.002

146 Jain S Wojdacz TK Su YH Challenges for the application of DNA methylation biomarkers in molecular diagnostic testing for cancer Expert Rev Mol Diagn 2013 13 283 94 23570406 10.1586/erm.13.9

147 Roy D Tiirikainen M Diagnostic Power of DNA Methylation Classifiers for Early Detection of Cancer Trends Cancer 2020 6 78 81 32061307 10.1016/j.trecan.2019.12.006 PMC7188195

148 Papanicolau-Sengos A Aldape K DNA Methylation Profiling: An Emerging Paradigm for Cancer Diagnosis Annu Rev Pathol 2022 17 295 321 34736341 10.1146/annurev-pathol-042220-022304

149 Karlstrom L Kelly KA Roux-Y gastrectomy for chronic gastric atony Am J Surg 1989 157 44 9 2910126 10.1016/0002-9610(89)90418-2

150 Chouhan H Ferrandon S DeVecchio J Kalady MF Church JM A Changing Spectrum of Colorectal Cancer Biology With Age: Implications for the Young Patient Dis Colon Rectum 2019 62 21 6 30394984 10.1097/DCR.0000000000001188

151 Li SY Wu HC Mai HF Zhen JX Li GS Chen SJ Microarray-based analysis of whole-genome DNA methylation profiling in early detection of breast cancer J Cell Biochem 2019 120 658 70 30203578 10.1002/jcb.27423

152 Williams KE Jawale RM Schneider SS Otis CN Pentecost BT Arcaro KF DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence J Cell Biochem 2019 120 738 55 30230580 10.1002/jcb.27431

153 Park AK Kim P Ballester LY Esquenazi Y Zhao Z Subtype-specific signaling pathways and genomic aberrations associated with prognosis of glioblastoma Neuro Oncol 2019 21 59 70 30053126 10.1093/neuonc/noy120 PMC6303485

154 Feng J Zhang Y She X Sun Y Fan L Ren X Hypermethylated gene ANKDD1A is a candidate tumor suppressor that interacts with FIH1 and decreases HIF1α stability to inhibit cell autophagy in the glioblastoma multiforme hypoxia microenvironment Oncogene 2019 38 103 19 30082910 10.1038/s41388-018-0423-9 PMC6318269

155 Liu J Jiang J Mo J Liu D Cao D Wang H Global DNA 5-Hydroxymethylcytosine and 5-Formylcytosine Contents Are Decreased in the Early Stage of Hepatocellular Carcinoma Hepatology 2019 69 196 208 30070373 10.1002/hep.30146

156 Nakamura M Chiba T Kanayama K Kanzaki H Saito T Kusakabe Y Epigenetic dysregulation in hepatocellular carcinoma: an up-to-date review Hepatol Res 2019 49 3 13 30238570 10.1111/hepr.13250

157 Wang L Fan Y Zhang L Li L Kuang G Luo C Classic SRY-box protein SOX7 functions as a tumor suppressor regulating WNT signaling and is methylated in renal cell carcinoma Faseb j 2019 33 254 63 29957056 10.1096/fj.201701453RR

158 Grube WA Liming KW ATTACHMENT AND BIOBEHAVIORAL CATCH-UP: A SYSTEMATIC REVIEW Infant Ment Health J 2018 39 656 73 30365173 10.1002/imhj.21745

159 Mariella E Grasso G Miotto M Buzo K Reilly NM Andrei P Transcriptome-wide gene expression outlier analysis pinpoints therapeutic vulnerabilities in colorectal cancer Mol Oncol 2024 18 1460 1485 38468448 10.1002/1878-0261.13622 PMC11161737

160 Ajithkumar P Vasantharajan SS Pattison S McCall JL Rodger EJ Chatterjee A Exploring Potential Epigenetic Biomarkers for Colorectal Cancer Metastasis Int J Mol Sci 2024 25 874 38255946 10.3390/ijms25020874 PMC10815915

161 Yasui K Toshima T Inada R Umeda Y Yano S Tanioka H Circulating cell-free DNA methylation patterns as non-invasive biomarkers to monitor colorectal cancer treatment efficacy without referencing primary site mutation profiles Mol Cancer 2024 23 1 38172877 10.1186/s12943-023-01910-y PMC10762960

162 Ben-Ami R Wang QL Zhang J Supplee JG Fahrmann JF Lehmann-Werman R Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer Gut 2024 73 639 48 38123998 10.1136/gutjnl-2023-331074 PMC10958271

163 Sorm F Vesely J THE ACTIVITY OF A NEW ANTIMETABOLITE, 5-AZACYTIDINE, AGAINST LYMPHOID LEUKAEMIA IN AK MICE Neoplasma 1964 11 123 30 14160691

164 Mizuno S Chijiwa T Okamura T Akashi K Fukumaki Y Niho Y Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia Blood 2001 97 1172 9 11222358 10.1182/blood.v97.5.1172

165 Stresemann C Lyko F Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine Int J Cancer 2008 123 8 13 18425818 10.1002/ijc.23607

166 Kurahashi Y Watanabe T Yamamoto Y Ureshino H Kamachi K Yoshida-Sakai N Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL Blood Adv 2023 7 1545 59 36516085 10.1182/bloodadvances.2022008362 PMC10130614

167 Derissen EJ Beijnen JH Schellens JH Concise drug review: azacitidine and decitabine Oncologist 2013 18 619 24 23671007 10.1634/theoncologist.2012-0465 PMC3662854

168 Šimoničová K Janotka Ľ Kavcová H Sulová Z Breier A Messingerova L Different mechanisms of drug resistance to hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukemia Drug Resist Updat 2022 61 100805 35227933 10.1016/j.drup.2022.100805

169 Navada SC Steinmann J Lübbert M Silverman LR Clinical development of demethylating agents in hematology J Clin Invest 2014 124 40 6 24382388 10.1172/JCI69739 PMC3871232

170 Lübbert M Suciu S Baila L Rüter BH Platzbecker U Giagounidis A Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group J Clin Oncol 2011 29 1987 96 21483003 10.1200/JCO.2010.30.9245

171 Flis S Gnyszka A Misiewicz-Krzemińska I Spławiński J Decytabine enhances cytotoxicity induced by oxaliplatin and 5-fluorouracil in the colorectal cancer cell line Colo-205 Cancer Cell Int 2009 9 10 19397792 10.1186/1475-2867-9-10 PMC2683807

172 Flis S Gnyszka A Flis K DNA methyltransferase inhibitors improve the effect of chemotherapeutic agents in SW48 and HT-29 colorectal cancer cells PLoS One 2014 9 e92305 24676085 10.1371/journal.pone.0092305 PMC3967992

173 De Carvalho Fischer C Hu Y Morreale M Lin WY Wali A Thakar M Treatment with epigenetic agents profoundly inhibits tumor growth in leiomyosarcoma Oncotarget 2018 9 19379 95 29721210 10.18632/oncotarget.25056 PMC5922404

174 Pulliam N Fang F Ozes AR Tang J Adewuyi A Keer H An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations Clin Cancer Res 2018 24 3163 75 29615458 10.1158/1078-0432.CCR-18-0204 PMC7003715

175 Travers M Brown SM Dunworth M Holbert CE Wiehagen KR Bachman KE DFMO and 5-Azacytidine Increase M1 Macrophages in the Tumor Microenvironment of Murine Ovarian Cancer Cancer Res 2019 79 3445 54 31088836 10.1158/0008-5472.CAN-18-4018 PMC6606334

176 Allfrey VG Mirsky AE Structural Modifications of Histones and their Possible Role in the Regulation of RNA Synthesis Science 1964 144 559 10.1126/science.144.3618.559 17836360

177 Kelly RDW Stengel KR Chandru A Johnson LC Hiebert SW Cowley SM Histone deacetylases maintain expression of the pluripotent gene network via recruitment of RNA polymerase II to coding and noncoding loci Genome Res 2024 34 34 46 38290976 10.1101/gr.278050.123 PMC10903948

178 Xu L Yan X Wang J Zhao Y Liu Q Fu J The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis Int J Mol Sci 2023 24 15066 37894746 10.3390/ijms242015066 PMC10606123

179 Cheshmazar N Hamzeh-Mivehroud M Nozad Charoudeh H Hemmati S Melesina J Dastmalchi S Current trends in development of HDAC-based chemotherapeutics Life Sci 2022 308 120946 36096240 10.1016/j.lfs.2022.120946

180 Mercurio C Minucci S Pelicci PG Histone deacetylases and epigenetic therapies of hematological malignancies Pharmacol Res 2010 62 18 34 20219679 10.1016/j.phrs.2010.02.010

181 Grant PA A tale of histone modifications Genome Biol 2001 2 Reviews0003 11305943 10.1186/gb-2001-2-4-reviews0003 PMC138925

182 Biersack B Nitzsche B Höpfner M Immunomodulatory properties of HDAC6 inhibitors in cancer diseases: New chances for sophisticated drug design and treatment optimization Semin Cell Dev Biol 2024 154 286 94 36127263 10.1016/j.semcdb.2022.09.009

183 Topper MJ Vaz M Chiappinelli KB DeStefano Shields CE Niknafs N Yen RC Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer Cell 2017 171 1284 300.e21 29195073 10.1016/j.cell.2017.10.022 PMC5808406

184 Bruyer A Maes K Herviou L Kassambara A Seckinger A Cartron G DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells Br J Cancer 2018 118 1062 73 29500406 10.1038/s41416-018-0025-x PMC5931098

185 Ushio R Hiroi M Matsumoto A Mori K Yamamoto N Ohmori Y Enhanced Cytotoxic Effects in Human Oral Squamous Cell Carcinoma Cells Treated with Combined Methyltransferase Inhibitors and Histone Deacetylase Inhibitors Biomedicines 2022 10 763 35453513 10.3390/biomedicines10040763 PMC9029187

186 Salahuddin A Ghanem H Omran GA Helmy MW Epigenetic restoration and activation of ERβ: an inspiring approach for treatment of triple-negative breast cancer Med Oncol 2022 39 150 35843988 10.1007/s12032-022-01765-1 PMC9288957

187 Szczepanek J Skorupa M Jarkiewicz-Tretyn J Cybulski C Tretyn A Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA Int J Mol Sci 2023 24 7235 37108398 10.3390/ijms24087235 PMC10138995

188 Hong H Sui C Qian T Xu X Zhu X Fei Q Long noncoding RNA LINC00460 conduces to tumor growth and metastasis of hepatocellular carcinoma through miR-342-3p-dependent AGR2 up-regulation Aging (Albany NY) 2020 12 10544 55 32493835 10.18632/aging.103278 PMC7346032

189 Fresquet V Garcia-Barchino MJ Larrayoz M Celay J Vicente C Fernandez-Galilea M Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death Cancer Discov 2021 11 1268 85 33355179 10.1158/2159-8290.CD-20-1065

190 Lee AV Nestler KA Chiappinelli KB Therapeutic targeting of DNA methylation alterations in cancer Pharmacol Ther 2024 258 108640 38570075 10.1016/j.pharmthera.2024.108640

191 Niinuma T Kitajima H Yamamoto E Maruyama R Aoki H Harada T An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST Anticancer Res 2021 41 2817 28 34083271 10.21873/anticanres.15062

192 Varambally S Dhanasekaran SM Zhou M Barrette TR Kumar-Sinha C Sanda MG The polycomb group protein EZH2 is involved in progression of prostate cancer Nature 2002 419 624 9 12374981 10.1038/nature01075

193 Sneeringer CJ Scott MP Kuntz KW Knutson SK Pollock RM Richon VM Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas Proc Natl Acad Sci U S A 2010 107 20980 5 21078963 10.1073/pnas.1012525107 PMC3000297

194 Kleer CG Cao Q Varambally S Shen R Ota I Tomlins SA EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells Proc Natl Acad Sci U S A 2003 100 11606 11 14500907 10.1073/pnas.1933744100 PMC208805

195 Poirier JT Gardner EE Connis N Moreira AL de Stanchina E Hann CL DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2 Oncogene 2015 34 5869 78 25746006 10.1038/onc.2015.38 PMC4564363

196 Feng S Marhon SA Sokolowski DJ D'Costa A Soares F Mehdipour P Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways Nat Commun 2024 15 9321 39472584 10.1038/s41467-024-53515-8 PMC11522499

197 Deblois G Tonekaboni SAM Grillo G Martinez C Kao YI Tai F Epigenetic Switch-Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer Cancer Discov 2020 10 1312 29 32546577 10.1158/2159-8290.CD-19-1493

198 Li H Chiappinelli KB Guzzetta AA Easwaran H Yen RW Vatapalli R Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers Oncotarget 2014 5 587 98 24583822 10.18632/oncotarget.1782 PMC3996658

199 Chen S Xie P Cowan M Huang H Cardenas H Keathley R Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer J Clin Invest 2022 132 e158800 35671108 10.1172/JCI158800 PMC9282926

200 Tan WW Allred JB Moreno-Aspitia A Northfelt DW Ingle JN Goetz MP Phase I Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients Clin Breast Cancer 2016 16 82 6 26774555 10.1016/j.clbc.2015.11.003 PMC5567753

201 Gatti-Mays ME Gameiro SR Ozawa Y Knudson KM Hicks KC Palena C Improving the Odds in Advanced Breast Cancer With Combination Immunotherapy: Stepwise Addition of Vaccine, Immune Checkpoint Inhibitor, Chemotherapy, and HDAC Inhibitor in Advanced Stage Breast Cancer Front Oncol 2020 10 581801 33747894 10.3389/fonc.2020.581801 PMC7977003

202 Masuda N Tamura K Yasojima H Shimomura A Sawaki M Lee MJ Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer BMC Cancer 2021 21 1269 34819039 10.1186/s12885-021-08973-4 PMC8611843

203 Connolly RM Zhao F Miller KD Lee MJ Piekarz RL Smith KL E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group J Clin Oncol 2021 39 3171 81 34357781 10.1200/JCO.21.00944 PMC8478386

204 Connolly RM Rudek MA Piekarz R Entinostat: a promising treatment option for patients with advanced breast cancer Future Oncol 2017 13 1137 48 28326839 10.2217/fon-2016-0526 PMC5618943

205 Wang J Zhang Q Li Q Mu Y Jing J Li H Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer Target Oncol 2021 16 591 9 34196874 10.1007/s11523-021-00823-4 PMC8484140

206 Zeleke TZ Pan Q Chiuzan C Onishi M Li Y Tan H Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer Nat Cancer 2023 4 257 75 36585452 10.1038/s43018-022-00489-5 PMC9992270

207 Oki Y Kelly KR Flinn I Patel MR Gharavi R Ma A CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial Haematologica 2017 102 1923 30 28860342 10.3324/haematol.2017.172882 PMC5664396

208 Younes A Berdeja JG Patel MR Flinn I Gerecitano JF Neelapu SS Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial Lancet Oncol 2016 17 622 31 27049457 10.1016/S1470-2045(15)00584-7 PMC5494693

209 Amengual JE Clark-Garvey S Kalac M Scotto L Marchi E Neylon E Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma Blood 2013 122 2104 13 23913470 10.1182/blood-2013-02-485441

210 Iyer SP Huen A Ai WZ Jagadeesh D Lechowicz MJ Okada C Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study Haematologica 2024 109 209 19 37439343 10.3324/haematol.2022.281875 PMC10772524

211 Huijberts S Wang L de Oliveira RL Rosing H Nuijen B Beijnen J Vorinostat in patients with resistant BRAF(V600E) mutated advanced melanoma: a proof of concept study Future Oncol 2020 16 619 29 32125175 10.2217/fon-2020-0023

212 Weber JS Levinson BA Laino AS Pavlick AC Woods DM Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma Melanoma Res 2022 32 324 33 35678233 10.1097/CMR.0000000000000818 PMC9444873

213 Ligon JA Sundby RT Wedekind MF Arnaldez FI Del Rivero J Wiener L A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma Clin Cancer Res 2023 29 341 8 36302175 10.1158/1078-0432.CCR-22-2168 PMC9851965

214 Woyach JA Kloos RT Ringel MD Arbogast D Collamore M Zwiebel JA Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma J Clin Endocrinol Metab 2009 94 164 70 18854394 10.1210/jc.2008-1631 PMC2630867

215 Wood A George S Adra N Chintala S Damayanti N Pili R Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma Invest New Drugs 2020 38 1108 16 31654285 10.1007/s10637-019-00864-7 PMC7182475

216 Giaccone G Rajan A Berman A Kelly RJ Szabo E Lopez-Chavez A Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors J Clin Oncol 2011 29 2052 9 21502553 10.1200/JCO.2010.32.4467 PMC3107761

217 Gharwan H Tomita Y Lee MJ Thomas A Berman A Giaccone G Alterations of immune cell subsets in relapsed, thymoma-associated minimal change disease: A case report Oncol Lett 2015 10 1155 8 26622643 10.3892/ol.2015.3325 PMC4509017

218 Cheng H Xie Z Jones WP Wei XT Liu Z Wang D Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents Aaps j 2016 18 737 45 26943915 10.1208/s12248-016-9876-3 PMC5256597

219 Welling DB Collier KA Burns SS Oblinger JL Shu E Miles-Markley BA Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas Laryngoscope Investig Otolaryngol 2021 6 1008 19 10.1002/lio2.643 PMC8513424 34667843

220 Eigl BJ North S Winquist E Finch D Wood L Sridhar SS A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195 Invest New Drugs 2015 33 969 76 25983041 10.1007/s10637-015-0252-4

221 Johnson ML Strauss J Patel MR Garon EB Eaton KD Neskorik T Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study Clin Lung Cancer 2023 24 218 27 36890020 10.1016/j.cllc.2023.01.013

222 Sheikh TN Chen X Xu X McGuire JT Ingham M Lu C Growth Inhibition and Induction of Innate Immune Signaling of Chondrosarcomas with Epigenetic Inhibitors Mol Cancer Ther 2021 20 2362 71 34552007 10.1158/1535-7163.MCT-21-0066 PMC8643315

223 Siegel DS Dimopoulos M Jagannath S Goldschmidt H Durrant S Kaufman JL VANTAGE 095: An International, Multicenter, Open-Label Study of Vorinostat (MK-0683) in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma Clin Lymphoma Myeloma Leuk 2016 16 329 34.e1 27025160 10.1016/j.clml.2016.02.042

224 Yee AJ Bensinger WI Supko JG Voorhees PM Berdeja JG Richardson PG Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial Lancet Oncol 2016 17 1569 78 27646843 10.1016/S1470-2045(16)30375-8

225 Maly JJ Christian BA Zhu X Wei L Sexton JL Jaglowski SM A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma Clin Lymphoma Myeloma Leuk 2017 17 347 53 28622959 10.1016/j.clml.2017.05.008 PMC6033275

226 Zhou X Singh M Sanz Santos G Guerlavais V Carvajal LA Aivado M Pharmacologic Activation of p53 Triggers Viral Mimicry Response Thereby Abolishing Tumor Immune Evasion and Promoting Antitumor Immunity Cancer Discov 2021 11 3090 105 34230007 10.1158/2159-8290.CD-20-1741 PMC9414294

227 Jones PA Ohtani H Chakravarthy A De Carvalho DD Epigenetic therapy in immune-oncology Nat Rev Cancer 2019 19 151 61 30723290 10.1038/s41568-019-0109-9

228 Chen R Ishak CA De Carvalho DD Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis Cancer Discov 2021 11 2707 25 34649957 10.1158/2159-8290.CD-21-0506

229 Tao H Jin C Zhou L Deng Z Li X Dang W PRMT1 Inhibition Activates the Interferon Pathway to Potentiate Antitumor Immunity and Enhance Checkpoint Blockade Efficacy in Melanoma Cancer Res 2024 84 419 33 37991725 10.1158/0008-5472.CAN-23-1082

230 Xu B He Y Wu X Luo C Liu A Zhang J Exploration of the correlations between interferon-γ in patient serum and HEPACAM in bladder transitional cell carcinoma, and the interferon-γ mechanism inhibiting BIU-87 proliferation J Urol 2012 188 1346 53 22906662 10.1016/j.juro.2012.06.005

231 Yoon N Park MS Shigemoto T Peltier G Lee RH Activated human mesenchymal stem/stromal cells suppress metastatic features of MDA-MB-231 cells by secreting IFN-β Cell Death Dis 2016 7 e2191 27077807 10.1038/cddis.2016.90 PMC4855669

232 Dunn GP Bruce AT Sheehan KC Shankaran V Uppaluri R Bui JD A critical function for type I interferons in cancer immunoediting Nat Immunol 2005 6 722 9 15951814 10.1038/ni1213

233 Joffre OP Segura E Savina A Amigorena S Cross-presentation by dendritic cells Nat Rev Immunol 2012 12 557 69 22790179 10.1038/nri3254

234 de Cubas AA Dunker W Zaninovich A Hongo RA Bhatia A Panda A DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer JCI Insight 2020 5 e137569 32493845 10.1172/jci.insight.137569 PMC7308050

235 Choy L Norris S Wu X Kolumam G Firestone A Settleman J Inhibition of Aurora Kinase Induces Endogenous Retroelements to Induce a Type I/III IFN Response via RIG-I Cancer Res Commun 2024 4 540 55 38358346 10.1158/2767-9764.CRC-23-0432 PMC10896070

236 Widschwendter M Jones PA DNA methylation and breast carcinogenesis Oncogene 2002 21 5462 82 12154408 10.1038/sj.onc.1205606

237 Lee JH Park SJ Abraham SC Seo JS Nam JH Choi C Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas Oncogene 2004 23 4646 54 15064707 10.1038/sj.onc.1207588

238 Hu A Sun L Lin H Liao Y Yang H Mao Y Harnessing innate immune pathways for therapeutic advancement in cancer Signal Transduct Target Ther 2024 9 68 38523155 10.1038/s41392-024-01765-9 PMC10961329

239 Liang Y Wang L Ma P Ju D Zhao M Shi Y Enhancing anti-tumor immune responses through combination therapies: epigenetic drugs and immune checkpoint inhibitors Front Immunol 2023 14 1308264 38077327 10.3389/fimmu.2023.1308264 PMC10704038

240 Cribbs AP Terlecki-Zaniewicz S Philpott M Baardman J Ahern D Lindow M Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism Proc Natl Acad Sci U S A 2020 117 6056 66 32123118 10.1073/pnas.1919893117 PMC7084125

241 Henning AN Roychoudhuri R Restifo NP Epigenetic control of CD8(+) T cell differentiation Nat Rev Immunol 2018 18 340 56 29379213 10.1038/nri.2017.146 PMC6327307

242 Shreeve N Depierreux D Hawkes D Traherne JA Sovio U Huhn O The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice Immunity 2021 54 1231 44.e4 33887202 10.1016/j.immuni.2021.03.021 PMC8211638

243 Avella Patino DM Radhakrishnan V Suvilesh KN Manjunath Y Li G Kimchi ET Epigenetic Regulation of Cancer Immune Cells Semin Cancer Biol 2022 83 377 83 34182142 10.1016/j.semcancer.2021.06.022

244 Chen Z Yang X Chen Z Li M Wang W Yang R A new histone deacetylase inhibitor remodels the tumor microenvironment by deletion of polymorphonuclear myeloid-derived suppressor cells and sensitizes prostate cancer to immunotherapy BMC Med 2023 21 402 37880708 10.1186/s12916-023-03094-0 PMC10601128

245 Gao T Sang X Huang X Gu P Liu J Liu Y Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer Acta Pharm Sin B 2023 13 4305 17 37799382 10.1016/j.apsb.2022.11.018 PMC10548052

246 Murphy S Rahmy S Gan D Liu G Zhu Y Manyak M Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy Cancer Res 2024 84 1597 1612 38588411 10.1158/0008-5472.CAN-23-2742 PMC11096030

247 Bu Z Yang J Zhang Y Luo T Fang C Liang X Sequential Ubiquitination and Phosphorylation Epigenetics Reshaping by MG132-Loaded Fe-MOF Disarms Treatment Resistance to Repulse Metastatic Colorectal Cancer Adv Sci (Weinh) 2023 10 e2301638 37303273 10.1002/advs.202301638 PMC10427397

248 Long S Huang G Ouyang M Xiao K Zhou H Hou A Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression Cell Death Dis 2023 14 365 37330579 10.1038/s41419-023-05878-x PMC10276877

249 Wang L Amoozgar Z Huang J Saleh MH Xing D Orsulic S Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model Cancer Immunol Res 2015 3 1030 41 26056145 10.1158/2326-6066.CIR-15-0073

250 Pang L Zhou F Liu Y Ali H Khan F Heimberger AB Epigenetic regulation of tumor immunity J Clin Invest 2024 134 e178540 39133578 10.1172/JCI178540 PMC11178542

251 Mabe NW Perry JA Malone CF Stegmaier K Pharmacological targeting of the cancer epigenome Nat Cancer 2024 5 844 65 38937652 10.1038/s43018-024-00777-2 PMC11936478

252 Qin S Xie B Wang Q Yang R Sun J Hu C New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication MedComm (2020) 2024 5 e551 38783893 10.1002/mco2.551 PMC11112485

253 Tang F Choy E Tu C Hornicek F Duan Z Therapeutic applications of histone deacetylase inhibitors in sarcoma Cancer Treat Rev 2017 59 33 45 28732326 10.1016/j.ctrv.2017.06.006 PMC5581728

254 Dai W Qiao X Fang Y Guo R Bai P Liu S Epigenetics-targeted drugs: current paradigms and future challenges Signal Transduct Target Ther 2024 9 332 39592582 10.1038/s41392-024-02039-0 PMC11627502

255 Morel D Jeffery D Aspeslagh S Almouzni G Postel-Vinay S Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise Nat Rev Clin Oncol 2020 17 91 107 31570827 10.1038/s41571-019-0267-4

256 Gray JE Saltos A Tanvetyanon T Haura EB Creelan B Antonia SJ Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non-Small Cell Lung Cancer Clin Cancer Res 2019 25 6623 32 31409616 10.1158/1078-0432.CCR-19-1305 PMC7234799

257 DuPage M Mazumdar C Schmidt LM Cheung AF Jacks T Expression of tumour-specific antigens underlies cancer immunoediting Nature 2012 482 405 9 22318517 10.1038/nature10803 PMC3288744

258 Dunn GP Bruce AT Ikeda H Old LJ Schreiber RD Cancer immunoediting: from immunosurveillance to tumor escape Nat Immunol 2002 3 991 8 12407406 10.1038/ni1102-991

259 Vesely MD Kershaw MH Schreiber RD Smyth MJ Natural innate and adaptive immunity to cancer Annu Rev Immunol 2011 29 235 71 21219185 10.1146/annurev-immunol-031210-101324

260 Beyer K Partecke LI Roetz F Fluhr H Weiss FU Heidecke CD LPS promotes resistance to TRAIL-induced apoptosis in pancreatic cancer Infect Agent Cancer 2017 12 30 28572836 10.1186/s13027-017-0139-4 PMC5450120

261 Roulois D Yau HL De Carvalho DD Pharmacological DNA demethylation: Implications for cancer immunotherapy Oncoimmunology 2016 5 e1090077 27141349 10.1080/2162402X.2015.1090077 PMC4839380

262 Connolly RM Li H Jankowitz RC Zhang Z Rudek MA Jeter SC Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study Clin Cancer Res 2017 23 2691 701 27979916 10.1158/1078-0432.CCR-16-1729 PMC5457329

263 Markus A Krekel D Lingens F Purification and some properties of component A of the 4-chlorophenylacetate 3,4-dioxygenase from Pseudomonas species strain CBS J Biol Chem 1986 261 12883 8 3745216

264 Li N Ma T Deng X Analysis of the coupling degree between regional logistics efficiency and economic development coordination PLoS One 2024 19 e0293175 38165925 10.1371/journal.pone.0293175 PMC10760707

265 Dumetier B Sauter C Hajmirza A Pernon B Aucagne R Fournier C Repeat Element Activation-Driven Inflammation: Role of NFκB and Implications in Normal Development and Cancer? Biomedicines 2022 10 3101 36551854 10.3390/biomedicines10123101 PMC9775655