Cancers in females, including the prevalent types such as breast, cervical, and ovarian cancer, pose a significant health threat to women and impose substantial economic and psychological burdens on families and societies. Breast cancer is one of the leading causes of death among postmenopausal women, accounting for approximately 23% of all cancer-related deaths, making it a global challenge (7). Unfortunately, due to a lack of awareness regarding self-examinations and the importance of regular clinical screenings, breast cancer is often diagnosed at an advanced stage.

In 1990, the global average mortality rate of breast cancer was estimated at 13.77 per 100,000 people. Between 1990 and 2015, the mortality rate increased annually by 0.7 per 100,000 people (8). In 2020, breast cancer claimed the lives of 685,000 women, accounting for 16% of all female cancer deaths, meaning that 1 in every 6 women who died of cancer succumbed to breast cancer. Since 2007, several high-income countries in North America, Europe, and Oceania have reported a continuous increase in the incidence of both premenopausal and postmenopausal breast cancers (9). In China, the cancer-related health burden continues to grow, with over 16 million people diagnosed with cancer annually and 12 million dying from it. Similar to most countries, breast cancer has become the most common cancer among Chinese women. In 2014, China accounted for 12.2% of all newly diagnosed breast cancer cases worldwide, and breast cancer deaths in China accounted for 9.6% of the global total (10). In 2020, 416,371 Chinese women were diagnosed with breast cancer, accounting for 18% of all new breast cancer cases worldwide (11). It is projected that by 2040, the number of newly diagnosed breast cancer cases will increase by over 40%, reaching approximately 3 million cases annually. Simultaneously, the number of deaths from breast cancer is expected to increase by more than 50%, from 685,000 in 2020 to 1 million in 2040 (12). There is significant heterogeneity in the patterns of post-traumatic responses among breast cancer patients, with those undergoing treatment exhibiting varying degrees of post-traumatic stress symptoms and growth (13). Aerobic and mind-body exercises and comprehensive workout routines have been found to effectively improve the quality of life of women with breast cancer (14).

Cervical cancer is the third most common cancer among women globally, following breast and colorectal cancers, with approximately 569,000 new cases diagnosed annually (15). Epigenetic changes play a significant role in the development and metastasis of cervical cancer. In developing countries, cervical cancer is the most common type of cancer in women, accounting for approximately 25% of all cases of cancers in females (16). It is also the second leading cause of cancer-related death among women worldwide.

Approximately 570,000 new cases of cervical cancer were diagnosed in 2018, resulting in 311,000 deaths (17). By 2020, the number of new cervical cancer cases had risen to 604,127, with 341,831 deaths, accounting for 6.5% and 7.7% of all new cancer cases and deaths among women worldwide, respectively (18). Among the 31 countries analyzed, the majority (26 in the incidence analysis and 30 in the mortality analysis) experienced stable or declining incidence and mortality rates over the past decade (19). In Vietnam, cervical cancer is the seventh most common type of cancer among women and the most prevalent gynecological cancer, with an incidence rate of 7.1 per 100,000 people. Both incidence and mortality rates in Vietnam depicted a slight decline from 1999 to 2017. In South Korea, a significant decrease in the incidence has been reported, highlighting the effectiveness of cervical cancer prevention and control programs in reducing the incidence of the disease. However, in Japan, the incidence and mortality rates of cervical cancer among women of all ages are on the rise, and this trend is expected to continue in the absence of effective prevention and intervention measures (20). From 1990 to 2019, the overall risk of cervical cancer incidence in the Chinese population gradually increased, with the age of the high-incidence groups advancing, while the risk of death decreased. It is anticipated that the incidence rate will decrease in the coming year, although the mortality rate is expected to rise before eventually falling (21). Due to its large population, China accounted for 11.9% of cervical cancer deaths and 12.3% of the global incidence rate in 2017 (22). Cervical cancer can significantly affect the psychological health of patients. Anticipatory grief, which is closely related to the impact of cancer and the patient’s physical condition, may also be influenced by factors such as the nature of the event, the patient’s age, and their physical manifestations (23).

Ovarian cancer accounts for 3% of all cancers in females but is the fifth leading cause of cancer death among women, following lung, breast, colorectal, and pancreatic cancers. In 2016, there were an estimated 57,200 new cases of ovarian cancer and 27,200 deaths in China (24). In 2018, the United States reported approximately 22,240 new cases and 14,070 deaths from ovarian cancer (25). By 2020, ovarian cancer was responsible for 207,252 deaths worldwide. The disease is categorized into various subtypes, with serous carcinoma being the predominant histological subtype, accounting for 42.97% of all new ovarian cancer cases worldwide (26). High-quality population-based cancer registry data will enhance our understanding of the epidemiological characteristics of ovarian cancer and provide valuable insights into its prevention, screening, and treatment.

The incidence of ovarian cancer increases with age and is particularly high among women aged more than 50 years, especially postmenopausal women. This heightened risk is associated with cessation of ovulation and related physiological changes. Although ovarian cancer is more common in older women, it can occur at any age. Factors such as genetics, environment, and lifestyle also contribute to its development (27).

Epigenetics has become increasingly integral to oncology, evolving into a crucial aspect of cancer research. Early studies revealed that cancer development is driven by cumulative changes that affect genomic structure and function. While genetic mutations disrupt DNA sequences, epigenetic changes modulate gene expression programs that contribute to the acquisition of cancer hallmarks. DNA methylation and histone modifications are the primary epigenetic alterations observed (28). Transcriptional epigenetic regulation can be achieved through changes in DNA methylation, histone modifications, and chromatin remodeling. Growing evidence indicates that epigenetic dysregulation is a prevalent mechanism in cancer (29). Epigenetic abnormalities are recognized as markers of cancer onset and progression. Consequently, combination therapies that integrate epigenetic drugs or targets with immunotherapy can enhance antitumor immunity as an improved strategy for cancer management (30). Additionally, the close relationship between metabolism and epigenetics has been highlighted, suggesting that targeting these interactions may offer promising therapeutic strategies (31).

Consequently, epigenetics has become pivotal in modern cancer treatment strategies. Over the past decade, immunotherapy has emerged as the primary cancer treatment method. Despite its promise, most patients do not achieve complete recovery and may develop resistance to treatment. Addressing this challenge has become a major focus in oncological epigenetics. Recent studies have exhibited that the epigenetic characteristics of immune and cancer cells can serve as accurate predictors of response to immunotherapy. Furthermore, combining epigenetic drugs with immunotherapy has the potential to modulate responses to these treatments. This has led to the development of epigenetic combination therapies as a new direction for oncological research. Emerging evidence suggests that tumors often evade immune responses through various epigenetic mechanisms. Consequently, pharmacological modulation of epigenetic regulators could normalize impaired immune surveillance and trigger antitumor immune responses, offering new strategies for improving cancer treatment outcomes.

Molecular biomarkers commonly used to predict cancer responses to immunotherapy include Programmed Death-ligand 1 (PD-L1) expression (32), tumor-associated antigens (33), Human Leukocyte Antigen (HLA) expression (34), T Cell Receptor (TCR) repertoire assessment (35), tumor mutational burden and neoantigen identification (36), mismatch repair deficiencies, presence of tumor-infiltrating lymphocytes, and cells within the tumor microenvironment that may inhibit antitumor immune responses (37). Recent advances in cervical cancer biology have revealed that epigenetic changes are prevalent during the transformation and metastasis of the disease. Abnormal DNA methylation and histone modifications have been extensively studied in cervical cancer (38). Beyond cervical cancer, epigenetics also play a significant role in other cancers, such as lung cancer, which is characterized by well-defined genetic driver mutations and both global and locus-specific epigenetic modifications. Advances in molecular targeted therapy have transformed the treatment of gene-driven lung adenocarcinoma, although these cancers display genetically distinct subclones and exhibit phenotypic variability. While targeted therapies can produce rapid responses, changes in the epigenome can explain the heterogeneity in the initial responses and subsequent resistance to these treatments (39). In both hematologic malignancies and solid tumors, existing drugs often perform poorly against solid tumors, limiting their broader application. Therefore, it is crucial to uncover the mechanisms underlying resistance or insensitivity. Epigenetic tools may induce specific metabolic vulnerabilities in solid tumors, offering new opportunities for developing innovative combination treatment strategies (31). In hematologic malignancies, Branched-chain Amino Acid Transaminase 1 inhibitors have been found to effectively inhibit the proliferation of Enhancer Of Zeste Homolog 2-deficient leukemia-initiating cells (EZH2-deficient leukemia-initiating cells), both in vitro and in vivo. This inhibition is selective, sparing normal hematopoietic stem cells and hematopoietic processes. Moreover, inhibiting this metabolic pathway may also hold therapeutic potential for other hematologic malignancies with EZH2 mutations or dysregulation (40).

Epigenetic modifications refer to heritable yet reversible changes in gene expression that do not involve alterations in the DNA sequence. These modifications are crucial for regulating gene expression and are essential for controlling vital biological processes such as cell differentiation and embryonic development. In cancer, epigenetic reprogramming contributes to transcriptomic heterogeneity and significantly influences tumor development and progression. Unlike the slow process of genomic evolution, epigenetic changes occur rapidly, making them particularly prevalent in cancer cells. This rapid adaptability enables cancer cells to quickly adjust to environmental changes and develop mechanisms to evade immune surveillance and drug treatment. Therefore, a comprehensive study of epigenetic modifications is essential for understanding the mechanisms of cancer onset and progression as well as for developing more effective treatment strategies ( Table 1 ).

In cancer research, aberrations in epigenetic modifications have been observed across various types of tumors, including anomalies in DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) expression. These abnormal epigenetic changes can result in the overactivation of oncogenes or silencing of tumor suppressor genes, thereby promoting the growth, proliferation, and metastasis of cancer cells. Understanding the roles and mechanisms of these epigenetic modifications in cancer development is crucial for developing personalized and precise treatment strategies that can improve treatment outcomes and patient survival rates.

DNA methylation is a biochemical process in which methyl groups are covalently added to the 5-carbon of the cytosine ring of DNA molecules. This modification occurs in Archaea, bacteria, and eukaryotes. In eukaryotes, DNA methylation is a crucial epigenetic modification that regulates various biological processes, maintains gene expression stability, and affects health and disease (47). As one of the most important epigenetic markers, DNA methylation is reversible and mitotically heritable. It plays a key role in controlling local gene expression (48, 49) establishing and maintaining cellular identity (50, 51) and regulating mammalian embryonic development (52, 53) among other biological processes (54) (55). This includes imprinting, X-chromosome inactivation, and the silencing of repetitive DNA elements (49). As illustrated in Figure 1 , dysregulation of DNA methylation is associated with a range of human diseases, including autoimmune disorders, metabolic dysfunction, neurological conditions, and cancers (56).

Abnormal patterns of DNA methylation are hallmark features of cancer cells and are believed to be associated with tumorigenesis. High levels of methylation, often observed in transcriptional regulatory elements such as gene promoters and enhancers, particularly those of tumor suppressor genes, suggest that epigenetic mutations may play a critical role in tumor development. Numerous cancer suppressor genes silenced by high DNA methylation have been identified in tumor tissues (57). This methylation can lead to transcriptional silencing of these genes, thereby promoting malignant transformation. Moreover, DNA methylation can occur at various gene loci with different degrees and locations, potentially resulting in distinct regulatory effects on gene expression and biological processes. This differential methylation regulatory mechanism is crucial for normal cellular function and the onset of cancer (58).

It is estimated that 70%–80% of Cytosine-Phosphate-Guanine (CpG) sites in the mammalian genome are methylated (59), except in specific regions known as CpG islands (CGIs). CGIs are CpG-rich sequences that are approximately 1,000 bases long and are predominantly located at gene promoters (60, 61). Approximately 60% of human gene promoters contain CGIs (62). DNA methylation is established by DNA methyltransferases (DNMTs), with DNMT3A and DNMT3B being essential for initiating DNA methylation, whereas DNMT1 maintains methylation during DNA replication (63). The Ten-eleven translocation (TET) family of enzymes, comprising TET1, TET2, and TET3, initiates repair mechanisms by oxidizing 5-methylcytosine (5mC). This oxidation can lead to either replication-dependent dilution or base excision repair, depending on the involvement of thymine DNA glycosylase (TDG) (64). These processes counteract the actions of members of the DNMT family, thereby promoting active DNA demethylation. Genome-wide analyses revealed distinct DNA methylation patterns across different cell types, developmental stages, and responses to various stimuli (65).

Abnormal DNA methylation patterns are associated with various diseases, including cancer (66). In cancer cells, overall DNA methylation levels are often reduced, whereas CGIs are hypermethylated in a cancer-specific manner (67, 68). Histone modifications, chromatin remodeling, and transcription factors play crucial roles in regulating both genome-wide and site-specific DNA methylation (69, 70). This highlights the significant impact of epigenetic changes on cancer development and underscores the potential of targeted epigenetic therapies.

In every cell, DNA is packaged in histones to form nucleosomal core particles. These histones have tails with numerous residues that can undergo post-translational modifications (PTMs). Such modifications are crucial, as they influence chromatin architecture and nucleosome dynamics while regulating transcription and affecting essential processes such as DNA repair, replication, stability, and cellular state transitions. Recent studies have highlighted that modifications in the core regions of histones, in addition to the tail regions, play a significant role in directly impacting DNA-based biological processes, including transcriptional regulation and maintenance, genomic stability, and cellular functionality (71).

Histone PTMs are essential for various critical processes in an organism. Aberrant histone modifications are closely linked to the development of diseases, such as cancer. Research has demonstrated that histones can undergo at least 11 types of PTMs on more than 60 different amino acid residues. These include methylation, acetylation, propionylation, butyrylation, formylation, phosphorylation, ubiquitination, SUMOylation, guanidinylation, prolyl isomerization, and Adenosine Diphosphate-ribosylation (ADP-ribosylation). These diverse modification patterns can regulate the structure and function of histones, thereby influencing gene expression, chromatin structure, and overall cellular functionality (72).

Histone H1, the most differentiated and heterogeneous of the histones, undergoes PTMs that are associated with cancer, autoimmune diseases, and viral infections (73). Phosphorylation sites on histone H1 subtypes, particularly H1.1–H1.5 in breast cancer cell lines, are highly conserved among these variants. Studies suggest that phosphorylation primarily occurs in H1.2, H1.3, and H1.5 subtypes, with focal adhesion kinase (FAK) potentially catalyzing this modification. In breast cancer cells, elevated levels of tyrosine phosphorylation in these H1 subtypes compared to normal cells suggest that this modification is crucial for breast cancer progression. Additionally, H1 tyrosine phosphorylation correlated positively with the proliferative state of cells, indicating that H1Y70p (tyrosine phosphorylation at position 70 of H1) may be a key factor in defining the tumor phenotype. These findings highlight the potential role of H1 subtype tyrosine phosphorylation in cell proliferation and tumor development, with FAK emerging as a significant regulator of this process. This underscores the potential targets for future therapies aimed at breast cancer and other diseases, particularly in developing strategies to inhibit or modulate FAK activity (74).

Histone acetylation levels are regulated by a dynamic balance between histone acetyltransferases and histone deacetylases (HDACs). Acetylation is generally associated with active gene expression as it leads to the loosening of the chromatin structure, thereby facilitating access to the transcriptional machinery. Conversely, histone methylation can either inhibit or promote transcription depending on the specific amino acid residue that is methylated. For instance, methylation of histone H3 at positions 9 and 27 (H3K9 and H3K27) is typically linked to transcriptional repression, whereas methylation at position 4 (H3K4) is associated with transcriptional activation ( Figure 2 ) (75). Methylation is a common modification process that occurs on lysine and arginine residues, particularly at multiple sites on the N-terminal tails of histones. This modification can range from unmethylated to tri-methylated states, with each added methyl group potentially altering the functional characteristics of the genomic regions. Histone methyltransferases are responsible for adding methyl marks to the genome, whereas histone demethylases remove these marks. The balance between these processes influences chromatin structure and gene expression, thereby regulating the activity or silence (76). Both epigenetic and genetic alterations play a critical role in determining cell fate, contributing to cellular homeostasis, or promoting tumor genesis (77).

In eukaryotic genomes, approximately 90% of genes are transcribed, yet only 1%–2% of these transcriptional products encode proteins. Most transcribed genes produce ncRNAs, which, while transcribed from the genome, do not code for proteins. ncRNAs can be broadly categorized into two types: structural ncRNAs, which are integral to fundamental cellular architecture, and regulatory ncRNAs, which play roles in gene regulation. Based on their length, ncRNAs are classified as small ncRNAs (sncRNAs, 18–200 nt) and long ncRNAs (lncRNAs, > 200 nt).

The biogenesis and function of Small Interfering RNAs, MicroRNAs, and Piwi-interacting RNAs (siRNAs, miRNAs, and piRNAs) in eukaryotes have been extensively studied (78, 79). Both siRNAs and miRNAs are derived from double-stranded RNA precursors, primarily processed by RNase III enzymes, Dicer for siRNA, and both Drosha and Dicer for miRNA (78). In contrast, piRNA, predominantly found in animal germ cells, is produced from single-stranded RNA precursors through a process independent of Dicer and Drosha, involving a set of proteins for primary processing and an amplification mechanism known as the “ping-pong cycle” (80). The primary functions of siRNAs, miRNAs, and piRNAs depend on their base pairing with RNA and/or DNA targets, mediated by Argonaute (AGO) family proteins. These interactions lead to RNA-silencing effects, including post-transcriptional mRNA cleavage, decay, translational repression, and transcriptional silencing. siRNAs and miRNAs are associated with the AGO subfamily, whereas piRNAs are linked to the P-element-induced Wimpy Testis (PIWI) subfamily. Notably, AGO-dependent RNA silencing is generally considered to occur exclusively in eukaryotes (81).

lncRNAs are emerging as significant regulatory factors involved in gene expression and various physiological and pathological processes (82). Increasing evidence has highlighted their critical role in cancer formation and progression. lncRNAs can act as oncogenes or tumor suppressor genes, providing complex and precise regulation of cancer cell behavior, including proliferation, differentiation, invasion, and metastasis. Additionally, they play a role in modulating metabolic reprogramming in cancer cells (83) (84). lncRNAs are also crucial in regulating the transcription and translation of metabolism-related genes. They may function as molecular “decoys,” “scaffolds,” or competitive endogenous RNAs, influencing cancer metabolic reprogramming and contributing to the complexity of cancer metabolism (85).

tRNA-derived small RNAs (tsRNAs) originate from tRNA precursors in the nucleus and are frequently dysregulated in various cancers, particularly gynecological malignancies. tsRNAs can bind to both AGO proteins (such as miRNAs) and PIWI proteins (such as piRNAs), thereby playing significant regulatory roles in gene expression. They participate in both pre-transcriptional regulation (such as piRNAs) and post-transcriptional regulation (such as miRNAs). Similar to piRNAs, tsRNAs are single-stranded molecules that can interact with DNA and histone methylation mechanisms, indicating their role in the pre-transcriptional regulation of gene expression. Like miRNAs, ts-53 (formerly known as miR-3676) can interact with the 3’ untranslated region (3’ UTR) of TCL1, supporting its role in the post-transcriptional regulation of gene expression. Dysregulated tsRNAs have significant impacts on various malignancies, including gynecological cancers, and the biological functions of tRFs are Ago-dependent. In ovarian cancer, tRF5-Glu regulates the levels of Breast Cancer Anti-Estrogen Resistance 3 mRNA by directly binding to the 3′ UTR (86). In patients with colorectal, breast, and ovarian cancer and their corresponding cell lines, the expression levels of ts-101 and ts-46 are associated with chromatin structure, cell survival, proliferation, clonal growth, and apoptosis. Besides, the expression of tRFs is linked to oncogene activation and ovarian cancer progression (87). Reanalysis of existing RNA sequencing data from 180 serum samples, including 15 healthy controls, 46 benign, and 22 borderline tumors, and 97 patients with ovarian cancer, revealed that tsRNAs constituted a significant proportion of total small RNAs (ranging from 2.5% to 29.4%) and were not random degradation products in serum but were enriched for several specific types of related tRNAs (for instance, Glycine-Transfer RNA), which can predict abnormal cell proliferation with high accuracy (88). Another group using serum samples from ovarian cancer patients, healthy donors, and ovarian cancer cell lines exhibited differential expression of tRFs; the results indicated that tRF-03357 promoted proliferation, migration, and invasion of Ovary Adenocarcinoma 3 (SK-OV-3) cells and downregulated Homeobox Containing 1 (HMBOX1) (89). In cervical cancer, preliminary studies using biopsy samples exhibited significantly elevated expression of 5S Ribosomal RNA (5S rRNA), Transfer RNA (tRNA) arginine, and tRNA Sec in samples containing Human Papillomavirus Type 16 (HPV16) compared to HPV-negative biopsies (90). The role of tRNA/tiRNAs in endometrial cancer remains unexplored. However, these findings suggest that tsRNAs play important roles in gene expression regulation and may be key regulators of the onset and progression of cancer. Further research will help elucidate the specific functions and mechanisms of tsRNAs in cancer and provide a theoretical basis for developing tsRNA-based therapeutic strategies. Research on tsRNAs can deepen our understanding of the complexities of gene expression regulation and offer new targets and strategies for future cancer treatment (90, 91).

In 1942, Conrad Waddington coined the term “epigenetics” to describe heritable changes in phenotypes that occur without alterations in the genotype (92, 93). Today, epigenetics broadly refers to ‘heritable phenotypes arising from changes in chromosomes without altering the DNA sequence’ (94). Epigenetic regulation is crucial for development, cell fate determination, proliferation, genomic integrity, and fundamental transcriptional control. This regulation occurs at multiple levels, including DNA methylation, histone modifications, nucleosome remodeling, and regulation of the three-dimensional chromatin structure ( Figure 3 ) (95). The connection between cancer genetics and epigenetics is evident in the abnormal metabolic and biochemical pathways observed in cancer, along with mutations in genes that function as epigenetic regulators. Reversing these epigenetic changes has depicted significant efficacy in treating the early stages of various types of lymphomas and leukemia, with similar therapeutic outcomes observed in solid tumors (96). For instance, activation of Wingless-type (WNT) signaling is linked to the onset and progression of various cancers, including breast cancer. The epigenetic silencing of WNT antagonist genes (such as SFRP and DKK) contributes to the initiation of breast tumors (97). Mechanistically, silencing of these genes through DNA methylation is a principal cause of continuous WNT signal transduction in breast cancer and is associated with poor prognosis (98). These changes result in constitutive activation of β-catenin, leading to increased stem cell renewal and proliferation, which is linked to disease recurrence. In a study of 96 breast cancer samples, promoter methylation of the Dickkopf (DKK) family member DKK3 was found to be significantly enriched in tumors from patients with advanced disease, lymph node metastasis, and positive Estrogen Receptor alpha (ERα) status (42 of 47 samples were ER⁺) (99).

The repressive state of chromatin can be maintained throughout the cell cycle through specific histone modifications, DNA methylation, regulatory proteins, and non-coding RNAs (100). In multiple human cancers, the loss of function of active chromatin remodelers results in a more compact chromatin state. Moreover, in many tumor types, specific CpG island hypermethylation suppresses the expression of tumor suppressor genes (such as p16) and DNA mismatch repair genes (such as MLH1 and MSH2), thereby promoting cancer progression (101). In Isocitrate Dehydrogenase-mutant (IDH-mutant) gliomas, extensive DNA hypermethylation reduces the binding capacity of the transcriptional repressor, CCCTC-binding Factor (CTCF), leading to impaired insulator function. These functions are crucial for the regulation of gene expression (102). Various cues can trigger abnormal changes in chromatin state, making it either open or closed. These changes may activate oncogenes or disabled tumor suppressor genes, endowing cells with the six essential hallmarks of cancer (103).

Ovarian cancer, like many other cancers, is characterized by alterations in various epigenetic regulators, including Enhancer Of Zeste Homolog 2,SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin2/4, and AT-rich Interactive Domain-containing Protein 1A (EZH2, SMARCA2/4, and ARID1A). Dysregulation of these factors frequently disrupts transcriptional control mechanisms, leading to abnormal cell fate decisions and disturbances in the pathways related to cell senescence, death, and proliferation. These epigenetic modifications, often driven by mitotic processes, are considered promising therapeutic targets because of their reversible nature ( Figure 4 ) (104).

A meta-analysis involving 43 studies and 16,336 women found that DNA methylation testing exhibited higher specificity than HPV16/HPV18 genotyping or cytology tests used to identify ≥ Atypical Squamous Cells of Undetermined Significance (ASCUS) level atypical squamous cells. This makes DNA methylation testing a more effective tool for further triaging after the initial screening (105). Among women with high-risk HPV genotypes detected in cervical samples, DNA methylation testing for ≥ Cervical Intraepithelial Neoplasia Grade 2 (CIN2) demonstrated a relative sensitivity of 1.22 (95% confidence interval [CI]: 1.05–1.42) compared to HPV16/HPV18 genotyping and 0.81 (95% CI: 0.63–1.04) compared to ≥ ASCUS cytology. The relative specificities were 1.03 (95% CI: 0.94–1.13) and 1.25 (95% CI: 0.99–1.59), respectively.

Pituitary Homeobox 2 (PITX2) methylation predicts outcomes of adjuvant anthracycline chemotherapy in high-risk patients with lymph node-positive, estrogen receptor (ER) positive, and HER2-negative breast cancer (106, 107). The Therascreen PITX2 RGQ PCR test (QIAamp Cador Pathogen Mini Kit), a Capillary Electrophoresis-marked assay, is highly reliable and robust for determining the PITX2 promoter methylation status. This test is effective in predicting outcomes in high-risk patients with breast cancer undergoing anthracycline-based chemotherapy (hazard ratio 2.48; p < 0.001) (108).

Epigenetic modifications are defined as inheritable changes in gene activity that occur without alterations to the underlying DNA sequence (3). Fine-tuning gene expression programs through epigenetic factors is the principal molecular mechanism controlling key biological processes, such as cell differentiation and embryogenesis. Compelling evidence suggests that epigenetic reprogramming drives dynamic transcriptional heterogeneity observed in cancer (4). Among the various types of epigenetic modifications, DNA methylation is the most extensively studied in humans. Since its discovery in primary human tumors four years ago, comprehensive research has robustly demonstrated that changes in DNA methylation patterns are instrumental in orchestrating cancer progression and metastasis (5).

Distortions in epigenetic mechanisms can affect a wide range of physiological processes and often lead to pathological conditions (109). Various disease categories, including neuropathology (110) and oncology (111), have been associated with misregulated epigenetic control. In the context of cancer, epigenetic alterations are classified into three distinct yet interconnected categories: epigenetic regulators, modifiers, and mediators (112). Epigenetic modifiers are enzymes or protein complexes that directly add or remove chemical modifications to DNA or histones, making them critical targets for cancer development. Epigenetic mediators are responsible for transmitting epigenetic information or signals, usually working in conjunction with modifiers or during the subsequent phases of their effects. Epigenetic regulators are positioned upstream of modifiers, directing their activity and localization and disrupting specific epigenetic patterns linked to cellular differentiation (113). Abnormalities in these mechanisms, which act as connectors between environmental factors and the epigenome, increase susceptibility to cancer and accelerate its progression. The increasing focus on epigenetic alterations in cancer research, particularly their role in driving cancer hallmarks, has significantly influenced both research and therapeutic approaches (4).

Whole transcriptome analysis is essential for understanding genomic structure and function, identifying the genetic networks underlying cellular, physiological, biochemical, and biological systems, and establishing molecular biomarkers for diseases, pathogens, and environmental challenges (114). This approach aims to capture and quantify gene expression heterogeneity across various levels, from individual cells to tissues, organs, and the entire organism. It represents a critical initial step in characterizing and annotating the functions of genes or genomes revealed through DNA sequencing (115).

RNA methylation—a widespread phenomenon in both eukaryotes and prokaryotes—is a significant focus in epigenetics. To investigate cytosine methylation in RNA, several RNA sequencing-based techniques have been developed to detect methylation sites with single-nucleotide precision, with or without chemical treatment. One such method, bisulfite sequencing of RNA, is analogous to bisulfite sequencing used for DNA. This technique involves treating RNA with bisulfite to convert methylated cytosine into uracil. Schaefer and his team successfully utilized this method in combination with high-throughput sequencing to reveal RNA methylation patterns (116). For instance, Khoddami and colleagues employed two mammal-specific cytosine RNA methyltransferases (m5C-RMTs) and the cytosine analog 5-azacytidine (117, 118). They developed a method known as Aza-immunoprecipitation (Aza-IP), which stabilizes m5C-RMT and RNA binding in cell culture. These complexes were then extracted through immunoprecipitation and analyzed using high-throughput sequencing to study RNA methylation patterns. Similarly, the RNA methyltransferase Nsun2 has been utilized to develop a methylation individual-nucleotide-resolution crosslinking and immunoprecipitation method that detects cytosine methylation in RNA species (119).

Epigenetics play a crucial role in the treatment of cancers in females by regulating gene expression, which affects cellular differentiation and proliferation and consequently influences tumor development. Epigenetic modifications consist of three main components: DNA methylation, histone modifications, and non-coding RNA, all of which are primary influencers in tumor genesis. Among the most extensively studied, DNA methylation involves the addition of a methyl group to the 5’-carbon of cytosine residues within CpG dinucleotides. CpG dinucleotides are unevenly distributed across the mammalian genome and are predominantly clustered in CGIs, often found within gene promoters (190). During DNA replication, the TET family of enzymes triggers a series of repair mechanisms by oxidizing 5mC, which may involve replication-dependent dilution or base excision repair by TDG to counteract the actions of DNMTs, consequently promoting active DNA demethylation (58). Increased demethylation activity increases the probability of tumorigenesis. From a histone perspective, modifications affect chromatin structure and nucleosome dynamics, impacting DNA repair, replication, stability, and cell state transitions. Histone methyltransferases mark methyl groups in the genome, whereas histone demethylases are responsible for removing these marks. These interactions affect chromatin structure and gene expression, thereby regulating gene activity or silencing states (71). Cellular homeostasis and the onset of tumors are decisively influenced by epigenetic and genetic changes (72). Furthermore, lncRNAs play a crucial role in tumor formation by precisely regulating complex control mechanisms. Epigenetic markers vary across different cancers in females, but they affect physiological processes. Currently employed epigenetic technologies such as transcriptomics, through methods such as RNA bisulfite sequencing and Aza-IP, facilitate the detection of cytosine methylation in RNA, aiding genome sequencing. Current epigenetic-based treatments for cancers in females, such as CRISPR and the DepMap database, identify cancer cell vulnerabilities and provide synthetic guidance for targeted drugs, effectively treating female patients. Clinical studies have reported that epigenetic drugs play a significant role in in vitro experiments and clinical treatments. More types of these drugs will be produced and used for the treatment of patients with tumors in the future.

The history of cancer treatment dates back several centuries, with many early methods still in use today. Over the past sixty years, significant progress has been made in establishing cancer models and precision therapies. For instance, genomic testing technologies have assisted doctors in tailoring treatment plans based on the characteristics of a patient’s tumor, significantly improving the efficacy of targeted therapies. Epigenetic regulation plays a crucial role in cancer treatment: it enhances the effectiveness of targeted drugs by influencing gene expression in cancer cells. Furthermore, cancer cells often evade treatment through epigenetic alterations, and drugs targeting these changes (such as histone deacetylase inhibitors) can restore cellular sensitivity to chemotherapy and targeted therapies, overcoming drug resistance. Additionally, epigenetic analyses can identify specific biomarkers that aid in developing personalized treatment plans. Moreover, epigenetic regulation can also affect the immune response in the tumor microenvironment, enhancing the attacking capacity of immune cells and improving the efficacy of immunotherapy (191).

Next-generation sequencing (NGS) technologies comprise a series of advanced genomic sequencing methods that allow for high-throughput, rapid, and cost-effective sequencing of DNA and RNA. The advancement of this technology enables researchers to obtain gene expression data at the single-cell level, overcoming the limitations of traditional large-scale sequencing methods in cancer research. Through single-cell transcriptomics and spatial transcriptomics, researchers can more accurately pinpoint gene expression in specific cell types or tumor locations, laying the groundwork for precision therapy. However, current single-cell and spatial transcriptomics technologies still have limitations in resolution, only detecting highly expressed genes, which poses a significant challenge for detecting low-expressed genes. The application of next-generation sequencing technologies can reveal cell-specific gene activity, helping researchers gain deeper insights into the biological mechanisms of cancer, thereby reducing the risk of ineffective treatments. Furthermore, integrating transcriptomics, proteomics, and computational models will provide a more comprehensive perspective on gene regulation, driving breakthroughs in cancer therapy (192).

There are still many limitations to epigenetic research, particularly regarding technical constraints. For instance, the sodium bisulfite conversion method used for DNA methylation testing presents challenges. Sodium bisulfite-treated DNA templates are unstable and prone to degradation, which can lead to difficulties and errors during PCR amplification (193). To address this issue, scientists have developed alternative methods for methylation sequencing analysis, such as methyl-sensitive restriction enzyme (MRE) digestion and methylated DNA immunoprecipitation (MeDIP), followed by high-throughput sequencing (194). In MRE digestion and MeDIP methods, methylated DNA regions are subjected to specific restriction enzyme digestion or affinity enrichment and then analyzed by high-throughput sequencing. However, these techniques often yield low-resolution and limited genomic coverage results and may not effectively differentiate individual methylation backgrounds (195). Furthermore, some epigenetic modifications exhibit high dynamism and cellular heterogeneity, underscoring the need for technical advancements. From a data interpretation perspective, the data generated by epigenetic studies are vast and complex and require precise analysis and interpretation. Uncertainties regarding the function and significance of some modifications remain, and the heterogeneity of patient samples adds complexity to data interpretation. Using technologies such as CRISPR also requires a larger patient cohort to enhance data interpretation. Currently, Cas9 and Cas12a are the only CRISPR family members used for genome editing; however, research is underway to develop artificial variants of these proteins to recognize different protospacer adjacent motifs and target a broader range of genomic sequences (196). Therefore, gene editing technologies need to be applied more widely. While many epigenetic modifications and transcription factors, such as those involved in WNT signaling and DKK3 promoter methylation, have been identified, the functions of many others remain unknown. For instance, whether KLF14 influences macrophage immune function through glycolysis remains unknown (197). A deeper understanding of the normal and abnormal functions of these modifications is essential and requires further research. Despite these challenges and limitations, continued technological advancements and in-depth research are expected to resolve these issues and enhance our understanding of the significant role of epigenetics in biology and disease development.

Future research into the mechanisms of female cancer development and the impact of epigenetics on female cancers will become more profound. Currently, DNA methylation and histone acetylation are among the most studied epigenetic changes in cancer progression and drug resistance. For example, in estrogen receptor-positive (ER+) preclinical models, small molecule inhibitors have been explored, including histone deacetylase inhibitors (such as entinostat and vorinostat) and DNA hypomethylating compounds (such as decitabine and 5-azacytidine). These compounds are being studied as resensitizers for endocrine therapy (198) (199). Regarding uterine fibroids, additional findings suggest that MED12 mutations are true drivers of fibrotic transformation. MED12 can activate CycC-CDK8 in the kinase module, and its mechanism involves the direct binding of MED12 to CDK8. This binding relies on repeatedly mutated MED12 residues in uterine fibroids (200), which may alter the T-loop conformation and impair CDK8’s kinase activity. Studies have shown that pathogenic mutations in exon 2 of MED12 can disrupt CDK8/19 kinase activity in patients with uterine fibroids (200), revealing molecular defects associated with fibroids. Although MED12 can also regulate transcription independently of CDK8, its mutations are linked to multiple pathology-related signaling pathways (such as Wnt/β-catenin and AKT/mTOR), and future research will focus on their effects and regulatory mechanisms on these pathways (201).Additionally, recent research findings indicate that Cobimetinib exhibits effective anti-cervical cancer activity in multiple cell lines, and when used in combination with paclitaxel, it can synergistically inhibit the growth of cervical cancer cells. This inhibitory effect is achieved by suppressing the activation of the MAPK/ERK signaling pathway while inducing caspase-dependent apoptosis. Furthermore, paclitaxel activates ERK in cervical cancer cells, and this activation can be reversed by cobimetinib (202). Theoretically, it is hoped that the impact mechanisms of epigenetics on cancer development can be more clearly studied in the future, providing theoretical support for technological development. In terms of technology, gene knockout technologies like CRISPR and cell analysis technologies like OriPRINT should receive more attention and development, enabling every female cancer patient to receive targeted treatment and improve survival rates. Clinically, future research could conduct more clinical experiments and treatments on a larger number of female patients based on the safety of animal experiments and promote the development and application of more drugs related to epigenetic factors. In the future, it is hoped that female cancer patients will not only receive effective treatment but also see improvements in quality of life and life expectancy post-treatment. QALY is also an issue that future research institutions need to consider, where QALY principles combine life duration (mortality) and quality of life (morbidity) into a single standard of measurement (203). This combination allows for the comparison of various interventions in the healthcare sector (204). This study can provide new insights into the treatment of female cancers, offering new hope to female cancer patients with diverse treatment options. Starting from the basic principles of epigenetics, to the application of transcriptomics in cancer treatment, and finally to clinical practice, this study helps to uncover innovations in epigenetic approaches to female cancer treatments. Through studies on DNA methylation, histone sequencing, RNA sequencing, CHIP-seq, and other methods, the importance of epigenetics in female cancers has been demonstrated, promising further advancements in research on female cancers.

In the field of female oncology, epigenetics is crucial for the development of early diagnosis and treatment strategies (205). DNA methylation and histone modifications, as key epigenetic markers, play an important role in tumor development. Additionally, non-coding RNAs such as miRNA and lncRNA also play key roles in regulating gene expression (206) and have the potential to become new biomarkers or therapeutic targets. Changes in chromatin structure within tumor cells are also critical; studies on chromatin remodeling help deepen our understanding of the molecular mechanisms of cancer and may reveal new treatment strategies. Meanwhile, liquid biopsy technologies (207), by analyzing circulating tumor DNA (ctDNA) and RNA in blood (208) or other body fluids, provide a non-invasive method to detect tumors, monitor disease progression, and assess treatment effectiveness, demonstrating their huge potential in clinical applications. The comprehensive application of these technologies offers multiple avenues for further research into female cancers (209). Epigenetic mechanisms play a complex role in treating female-specific cancers like breast and ovarian cancer, including DNA methylation and histone modifications (210). A major challenge is how to precisely identify and target these modifications to effectively restore normal gene expression. There are also research gaps in the field of early detection of breast cancer. Although liquid biopsy has made progress in monitoring treatment efficacy and tumor resistance, it is still in the exploratory phase for early detection, particularly lacking comprehensive testing panels for specific gene methylation. Additionally, current studies often focus on single biomarkers (such as CDH1 and RASSF1) and have not established effective integrated gene panels that combine multiple biomarkers to improve detection sensitivity and specificity (211). Additionally, the epigenetic characteristics of cancer can change over time, affecting the progression of the disease and treatment response; how to track and utilize these dynamic changes for real-time assessment is also an urgent issue to address. At the same time, the variability in epigenetic characteristics among patients poses challenges to achieving personalized treatment plans, requiring precise genomic analysis to predict treatment responses and devise corresponding treatment plans (212). Based on these challenges, in the future, we can seek and validate new biomarkers that help predict patients’ responses to DNA methylation inhibitors, thereby improving treatment success rates. We can utilize technologies like liquid biopsies to dynamically monitor the epigenetic changes in cancer patients, adjust treatment plans in real time, and enhance the accuracy of treatment effects and prognosis predictions.