Epigenetics in lung cancer precision medicine: from bench to bedside—a narrative review

Introduction

Lung cancer is the most commonly diagnosed cancer, accounting for 12.4% (2.5 million cases) of all cancer cases worldwide and resulting in a high mortality rate of 18.7%, corresponding to 1.8 million deaths (1). Regardless of gender, lung cancer has been one of the leading causes of cancer death in the United States over the past few decades (1). It is considered a significant global economic burden, with annual management costs exceeding $20 billion in the USA (2,3). Lung cancer is primarily categorized into two histopathologic subtypes: small cell lung cancer (SCLC, 15%) (4) and non-small cell lung cancer (NSCLC, 85%). The latter is further categorized based on histological organization, including lung adenocarcinoma (LUAD, 40%), lung squamous cancer (LUSC, 20%), and large cell lung carcinoma (3%) (5,6).

Survival rates of patients with NSCLC has improved dramatically due to advances in systematic screening of high-risk populations using low-dose computed tomography (CT) and standard treatment strategies (7). The treatment options for lung cancer include surgery, radiation therapy, chemotherapy, targeted therapy, and immunotherapy (8,9). For patients with early-stage NSCLC [stage I, Tumor-Node-Metastasis (TNM) staging system], surgery and radiotherapy are the preferred methods. For stage II–III NSCLC patients, neoadjuvant chemotherapy combined with immunotherapy is recommended. For stage IB-IIIA NSCLC patients harboring epidermal growth factor receptor (EGFR) mutations or ALK fusions, complementary therapy with Osimertinib or Alectinib, respectively, is available. For those with advanced NSCLC (stage IV), the combination therapies involving immune checkpoint blockade (ICB) plus chemotherapy have been approved. If druggable genomic alterations are present, second-line targeted therapy should be considered (7). Specific treatment patterns and target medications are discussed in reviews published elsewhere (7,10). Moreover, an important component of immunotherapy, immune checkpoint inhibition (ICI) has emerged as a successful first-line treatment option for advanced lung cancer. For example, nivolumab, a programmed death-ligand 1 (PD-L1) blocking antibody, is approved for LUSC after failure of first-line treatment with platinum-based two-agent chemotherapy (also applicable to NSCLC). Pembrolizumab is used as a first-line treatment for patients with high PD-L1 expression, while atezolizumab is approved for advanced NSCLC patients who have experienced unfavorable progression after chemotherapy. Other immunotherapy approaches, including tumor vaccines, adoptive cell therapy, targeted antibodies, and oncolytic viruses, also have therapeutic potential in lung cancer (9).

Precision medicine refers to the stratified and personalized treatment of patients based on biomarkers derived from the disease-specific molecular profiles or high-throughput sequencing data, with the aim of maximizing clinical treatment benefits. Two key steps are required to translate this concept into clinical practice in oncology: genomic precision medicine and functional precision medicine. The former focuses on clustering patients and mining potential therapeutic targets, while the latter involves obtaining drug perturbation data from tumor-derived samples, offering valuable insights for clinical oncologists’ decision-making, which has achieved heartening progress (11,12). The history and key milestones of precision medicine have been detailed in the previous review (13). Prior to 2004, lung cancer was only distinguished into two subgroups based on the presence of KRAS mutations: mutant and non-mutant. However, the discovery of EGFR mutations and the clinical application of EGFR inhibitors marked a significant turning point, making precision medicine a reality in lung cancer starting in 2004 (14). EGFR inhibitors have become a first-line therapeutic option for NSCLC, and their combination with anti-angiogenic agents, chemotherapy, and immunotherapy promotes the diversity of therapeutic regimens to overcome low response towards therapy (15). Until now, numerous subtypes of genomic mutations in lung cancer have been reported (16). The use of genomic biomarkers to guide treatment is emerging in precision oncology for various types of cancer, including but not limited to colorectal cancer, breast cancer, hepatobiliary cancer, and thyroid cancer (17). Multiple mutations of the KRAS gene are found in approximately 14% of human solid tumors (18). The discovery and approval of specific small molecules targeting KRAS have paved the way for precise treatment in KRAS-mutated patients (19,20). Moreover, patients with different KRAS mutational types exhibit varying responses to immunotherapy, indicating that further stratification is needed (21-24). However, acquired drug resistance also occurs with the latest EGFR inhibitors (osimertinib and olmutinib) (25,26). Notably, this resistance is closely linked to epigenetic heterogeneity: sensitivity to these agents in EGFR-driven lung cancer models varies dramatically depending on distinct epigenetic states (27).

Dysregulation of epigenetic information, encompassing DNA modifications, histone modifications, RNA modifications, and noncoding RNAs, significantly affects tumor initiation, progression, metastasis, and drug resistance. By targeting regulators of the aforementioned epigenetic mechanisms, the clinical success of drugs represented by the DNA methyltransferases (DNMTs) inhibitors: Azacitidine and Decitabine, has inspired researchers to pursue precision medicine from the epigenetic perspectives (Table 1) (16,28). Although the role of epigenetic dysregulation in the context of precision lung oncology has gained attention and research interest is rising (29-31), there is a lack of a comprehensive review on the latest advances in epigenetic biology of lung cancer and its clinical implications. Our review based on epigenomics and epigenetic drug therapy would broaden insights in therapeutic decision making for precision lung oncology, even accelerates genomic precision medicine, and further contributes to functional precision medicine. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0324/rc).

Methods

This narrative review focused on epigenetics and precision medicine in lung cancer. Systematic literature retrieval was performed across PubMed and Web of Science Core Collection from database inception to January 31, 2026, supplemented by manual screening of reference lists from retrieved articles to identify additional valuable original papers and reviews. Search keywords included lung cancer, epigenetics and precision medicine, with further manual filtering for studies covering DNA methylation and histone modification. Eligibility criteria were as follows: (I) peer-reviewed articles published in English; (II) preclinical experimental studies and clinical cohort studies; (III) publications released by February 2026. J.Z. and Y.P. independently screened titles, abstracts and full texts, and any inconsistencies were settled via group discussion (Table 2).

Epigenetic dysregulation in lung cancer

Epigenetic information is represented by DNA modifications, histone modifications, RNA modifications, non-coding RNAs, and high-order chromatin structure (32). Here, we specifically focus on the roles of DNA modifications, histone modifications in lung cancer pathogenesis.

DNA methylation

A methyl group is added to the carbon atom in the fifth position of the cytosine of DNA to generate 5-methylcytosine (5mC) on DNA (33). 5mC is catalyzed by DNA methyltransferases (DNMTs), which transfer a methyl group from S-adenyl methionine (SAM) to cytosine. The DNMT family is divided into two groups: de novo DNMTs (DNMT3A, DNMT3B) and maintenance DNMT (DNMT1). The de novo DNMTs establish new methylation on unmodified DNA, while the DNMT1 functions to copy the DNA methylation state from the parental DNA strand to the newly synthesized daughter strand during DNA replication (33,34). The cytosine-phosphate-guanine (CpG) islands are some DNA regions enriched in CpG dinucleotides, mainly locating in promoter and exon regions. DNA hypermethylation of CpG islands in promoter regions typically represses transcription through various molecular mechanisms, such as inhibiting transcription factors binding to methylated DNA sequences, changing chromatin structure, and facilitating methylated DNA binding proteins to recruit transcriptional repressors (35). DNA demethylation is achieved by two distinct mechanisms: (I) inactivation of the maintenance DNA methylation machinery: inhibition or dysfunction of DNMT1 dilutes newly synthesized DNA methylation level; (II) DNA demethylase ten-eleven translocation (TET)-dependent demethylation: TET proteins catalyze and oxidate 5mC to 5-hydroxymethyl-cytosine (5hmC), and subsequently convert 5hmC to 5-formyl-cytosine (5fC) and then 5-carboxy-cytosine (5caC) (Figure 1). The 5fC and 5caC are reduced to unmodified cytosine by thymine DNA glycosylase (TDG) (36). Concurrently, the ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) facilitates the DMNTs-mediated methylation while inhibiting TET-mediated demethylation (37-39).

Figure 1 The molecular mechanism of DNA methylation (left) and the diagram of DNMT inhibitors (right). DNMT, DNA methyltransferase; TETs, ten-eleven translocations.

Abnormal DNA methylation is considered as a hallmark of NSCLC, with hypermethylation of oncogenes and hypomethylation of tumor suppressor genes commonly observed (40,41). The gene list with abnormal hypermethylated methylation in lung cancer and their biological functions can be found in a previous review (42). Abnormal methylation of tumor suppressor genes (p16INK4A, RARB2, RASSF1A, and SOX17) is found in lung cancer (43). Promoter methylation of the tumor suppressor gene p16INK4a leads to gene silence, which promotes cell proliferation in NSCLC and facilitates diagnosis in multiple solid cancers (44,45). Other tumor suppressor genes that are commonly hypermethylated in NSCLC include, but are not limited to, RASSF1A, SEMA3B, and PTEN (34,46). The previous literature has highlighted the important role of epigenetic regulation mechanisms (DNA methylation, histone methylation, and acetylation) in SCLC (47). How dysregulation of DNMTs and TETs affects pathologic progression in lung cancer has been summarized (34). In NSCLC, the hypermethylation of EPHB6 (48), HS3ST2 (49), and TMEM88 (50) facilitates cancer metastasis. Conversely, the hypomethylation of ELMO3 (51) and FAM83A (52) contributes to metastasis and poor prognosis, respectively. Compared with non-recurrent patients, recurrent lung cancer patients show significant hypomethylation in several oncogenic pathways, including but not limited to inflammatory response, epithelial-mesenchymal transitions, Rap1 signaling pathway, and ECM-receptor interaction (53). The downregulation of DNMT1 and/or DNMT3B triggers inhibitory proliferation and apoptosis through activating tumor suppressors (54). High DNMT3A expression is relevant to better patients’ prognosis, and DNMT3A methylates oncogenes to inhibit LUAD progression (55,56). TET1, a tumor suppressor in lung cancer, inhibits the key genes expression (XRCC1, OGG1, APEX1) of base excision repair (BER) pathway to alleviate DNA damage repair (57). TET1 also demethylates and transactivates tumor suppressor genes (SLIT2, ZNF382, and HOXA9) (58,59). Recently, TET2 deficiency demethylates and activates the NF-κB pathway to involve EGFR-TKI resistance in NSCLC (60).

Notably, DNA methylation exerts non-canonical biological functions by mediating gene transcriptional activation. On the one hand, it can be specifically recognized and bound by distinct transcription factors to trigger subsequent regulatory cascades and transcriptional events; on the other hand, it expels PRC2 complex from gene regulatory regions to eliminate repressive H3K27me3 modification and thereby boost transcription (61). In addition, promoter hypermethylation drives gene expression upregulation via three major mechanisms: hindering the recruitment of repressive transcription factors, rewiring the crosstalk between promoters and distal regulatory elements such as enhancers, silencers and insulators, and initiating transcription through alternative promoter usage (62).

Histone modification

Histone methylation

In addition to DNA methylation, histone modifications also play an important role in regulating chromatin structure and gene transcription by adding chemical groups (e.g., methyl, acetyl) to amino acid residues at histone tails (typically on histone H3 and H4). Methylation of histones on different lysine residues is subtly regulated by specific and paired histone lysine modification factors, mainly including histone lysine methyltransferases (KMT) and histone lysine demethylases (KDM) (63).

The principal and well-studied methylation sites on histones H3 and H4 include H3K4 (64), H3K9 (65-67), H3K27 (68), H3K36 (69,70), H3K79 (71), and H4K20 (72). More details of the “writer” (histone methyltransferases, generation), “reader” (methyl-lysine binding effectors, reorganization), and “eraser” (histone demethylases, elimination) for the above sites and their roles in lung cancer are as follows. Although the therapeutic targets related to histone modification in NSCLC have been depicted (73), we aim to refine the above context to lung cancer and update the molecular mechanisms from an epigenetic view (Figures 2,3).

Figure 2 Schematic summary of the roles of H3K4, H3K36, H3K9 and H3K27 methylation in lung cancer cells. Purple shading indicates methylation marks associated with transcriptional activation, while sky-blue shading denotes marks linked to transcriptional repression. Left panel: formation/establishment of each methylation mark; right panel: the biological functions of indicated modifications in lung cancer.

Figure 3 Schematic summary of the roles of H3K79, H4K20 methylation and histone acetylation in lung cancer cells. Purple shading indicates epigenetic marks associated with transcriptional activation. Left panel: formation/establishment of each epigenetic mark; right panel: the biological functions of indicated modifications in lung cancer tumor cells. EGFRi, epidermal growth factor receptor inhibitor; HDAC, histone lysine deacetylase; VEGF, vascular endothelial growth factor.

H3K4 methylation

H3K4 methylation, a marker of active transcription, is accomplished by Set1 family methyltransferases with the Su(var)3-9, Enhancer of Zeste, and Trithorax (SET) catalytic structural domain. In mammals, there are six Set1 methyltransferases: SETD1A/KMT2F, SETD1B/KMT2G, MLL1/KMT2A, MLL2/KMT2B, MLL3/KMT2C and MLL4/KMT2D (74). Demethylation of H3K4 is performed by six histone demethylases: two KDM1 family members [lysine-specific demethylase 1 (LSD1)/KDM1A and LSD2/KDM1B] and four KDM5 family members (JARID1A/KDM5A, JARID1B/KDM5B, JARID1C/KDM5C, and JARID1D/KDM5D) (75). Members of the KDM1 family specifically remove H3K4me1/2, whereas enzymes of the KDM5 family erase H3K4me1/2/3 (74). The readers of H3K4me3 mainly include CHD1, PHF2, BPTF (64,76).

KMT2C, with function-deficient mutation in NSCLC (5.8% in cBioPortal database) (77) and SCLC (12%) (78), related to poor prognosis, tumor proliferation and metabolic reprogramming (79-81), improves DNA repair through mediating H3K4 methylation and recruiting Ago2 at DNA damage sites (82). KMT2D is regarded as a tumor suppressor that frequently mutates in multiple solid cancers, including lung cancer and breast cancer, involving the regulation of glycolytic genes, EGFR-ERBB2 and RTK-RAS pathway (83). KMT2D deficiency, reduces PER2 expression in a super-enhancer dependent manner to relieve its inhibition on glycolytic genes, promoting glycolysis and tumorigenesis in LUAD models (84).

LSD1 is considered as a promising target in solid cancers, modulating cancer cell stemness by WNT, Notch, TGF-β, JAK/STAT, Hedgehog and PD-L1 signaling axis (85). LSD1, highly expressed in lung tumor tissues, is associated with poor prognosis, maintaining ferroptotic resistance through demethylating c-Myc and then upregulating c-Myc (86). LSD1 promotes tumor metastasis through demethylating SEPT6 in promoter region, which induces SEPT6-mediated TGF-β1 pathway activation in NSCLC (87). LSD1 suppresses TIMP3 expression by erasing H3K4me2 in its promoter to relieve the inhibitory effect of TIMP3 to pro-metastatic MMP2 and JNK, accelerating NSCLC progression (88). LSD1 facilitates LUAD progression through the activation of LSD1-integrin β3 axis and LSD1/PLK1 signaling pathway, respectively (89,90). Conversely, LSD1 demethylates H3K4me2 at the promoter of the inhibitory transcriptional factor REST to inhibit REST transcription, upregulating neuroendocrine markers expression and promoting SCLC progression (91). Interestingly, LSD1, the synthetic lethal partner of DNMT3A, is dedicated to the treatment vulnerability through targeting LSD1 in DNMT3A-deficient NSCLC (92). LSD2, demethylates H3K4me2 in the promoter region of tumor suppressor gene TFPI-2 and negatively modulates its expression, promoting SCLC progression (93).

KDM5A, also known as JARID1A or RBP2, modulates proliferation, cancer stem cell differentiation, cell senescence, motility, angiogenesis, and treatment resistance in various carcinomas (94). KDM5A upregulates p27 and downregulates cyclin D1 and ITGB1 to accelerate proliferation, invasion, metastasis, and cancer cells stemness in lung cancer cells (95-97). The KDM5A-mediated angiogenesis depends on the activation of PI3K/Akt/HIF-1α/VEGF signaling axis (96). KDM5B (also known as JARID1B), overexpressed in breast cancer, prostate cancer, and lung cancer (98-100), promotes lung cancer cell proliferation and invasion through upregulating the E2F/Rb axis and suppressing p53 expression, respectively (101,102).

H3K9 methylation

The potential HMTs methylating H3K9 include five members: Suppressor of variegation 3–9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1/2 (SETDB1/2), G9a and G9A-like protein (G9a-GLP) (65). SETDB1 generates mono-methylation, whereas SUV39H1 and SUV39H2 catalyze H3K9 di- and tri-methylation in heterochromatin (103,104). However, the role of SETDB2 remains elusive (65). Multiple proteins were reported to demethylate H3K9 methylation, including KDM1 (KDM1A, KDM1B), JHDM2/KDM3 (KDM3A, KDM3B, KDM3C), JHDM3/KDM4 (KDM4A-4F) and KDM7 (KDM7A, KDM7B/PHF8, KDM7C/PHF2) (76,105). H3K9 tri-methylation, recognized by the reader HP1 (heterochromatin protein 1), is one of the important histone characteristics of heterochromatin formation and transcriptional silencing (65,106).

The pro-tumorigenic or onco-suppressive roles of H3K9 methyltransferases are contingent upon specific cancer types and molecular contexts (107,108). SETDB1 is regarded as a tumor suppressor (109) and inhibits lung cancer metastasis via downregulating ANXA2 (110). The chimeric antigen receptor (CAR) T cell therapy is beneficial from knocking out SUV39H1 as this editing downregulated inhibitory receptors and T cell exhaustion biomarkers in a H3K9 methylation-dependent manner (111). Another study, in contrast, finds that SETDB1 induces H3K9me3 of anti-metastatic gene FOXA2 (silencing FOXA2) and recruits DNMT3A to facilitate DNA methylation, thus promoting tumor metastasis and progression in NSCLC, respectively (112). Silencing SETDB1 reshapes 3D genome organization and decreases H3K9me3 at euchromatic regions to alleviate proliferation and migration in LUAD cells (113). G9a-mediated H3K9me2 suppresses expression of tumor metastatic genes to attenuate cancer progression in LUAD models (114). Lamin B2 indirectly silences the E-cadherin gene (CDH1) through recruiting G9a to induce H3K9me2 in the CDH1 gene body, thus resulting in enhanced tumor cell migration in LUAD (115).

Dysfunction of KDM1A, KDM1B, KDM2A, KDM4C, or KDM6A is involved in tumorigenesis of lung cancer (116). Recruited by BRG1, KDM3A demethylates H3K9me2 in promoter to activate CCNB1 and LTBP2 transcription, augmenting lung cancer cell proliferation and migration (117). KDM3B, relevant to unfavorable recurrence-free survival in NSCLC, is upregulated in taxane-platin-resistant NSCLC cells (118). KDM4A, negatively regulated by miR-150 and SIRT2, promotes NSCLC cell proliferation (119,120). Meanwhile, KDM4A upregulates oncogenes’ expression (ADAM12, CXCL5, and JAG1) in a H3K9 methylation-dependent manner in lung cancer cells (121). KDM4A prevents cell senescence through transcriptionally inhibiting the tumor-suppressive CHD5/p53 axis in KRAS-mutated lung cancer (122). KDM4B correlates with poor prognosis of lung cancer patients (123). KDM4C, overexpressed in lung cancer tissues, enhances cancer cell migration and invasion through modulating CUL4A, p53 and p27 (124). Highly expressed in metastatic lung cancer tissues (125), deubiquitinated and stabilized by USP9X, KDM4C removes H3K9me3 at the promoter of TGF-β2 to upregulate its expression, thus activating the TGF-β2/Smad/ATM/Chk2 pathway to endow radio-resistance in lung cancer (126).

H3K27 methylation

H3K27 methylation is usually catalyzed by polycomb repressive complex 2 (PRC2), which contain four core subunits: Enhancer of Zeste Homolog 2 (EZH2), SUZ12, EED and RBBP4 (127). The monomethylated H3K27 is catalyzed by Trithorax-Related Protein 5/6 (ATXR5/6) in Arabidopsis, while all H3K27 methylation states are produced by PRC2 complex in mammalian cells (128). KDM6A(UTX)/KDM6B(JMJD3) and KDM7A gradually demethylate H3K27me3/2 and H3K27me2/1, respectively (127). The H3K27 methylation reader protein is bromo-adjacent homology (BAH)-plant homeodomain (PHD) domain containing protein BAH–PHD protein 1 (BP1) (129).

H3K27me3 is a well-known epigenetic marker of transcriptional gene silencing (130). The components of the PRC2 complex are often abnormally upregulated, with EZH2 being a well-studied oncogene in multiple carcinomas (131). The molecular mechanisms and therapeutic implications of EZH2 in lung cancer have been reviewed: EZH2, regulated by HOTAIR, RB1/E2Faxis and TGF-β1/MTA1/SOX4 axis, associating with therapy resistance and patient’s prognosis, involves numerous malignant phenotype (proliferation, cell cycle, EMT, metastasis, apoptosis and autophagy) through modulating p21/CDK1/CyclinB1 axis, VEGFA/AKT axis, TSC2/RHEB/mTOR axis and Bad/Puma axis (132). ZCCHC8, a subunit of nuclear exosome targeting (NEXT) complex, facilitates lung cancer progression through recruiting PRC2 to induce H3K27me3 in tumor suppressor SEMA5A (133). KDM6A maintains the neuroendocrine phenotype of SCLC through upregulating H3K27me3 and downregulating H3K4me1 at enhancers of neuroendocrine genes (134). Recently, NIPBL enhances oncogene RAD21 expression via recruiting KDM6B to attenuate H3K27 methylation, while NIPBL prevents EZH2 binding to RAD21-located PI3K promoter, which causes the activation of PI3K in NSCLC (135).

H3K36 methylation

H3K36 methyltransferases are present in human cells, mainly including NSD1/KMT3B, NSD2/KMT3G, NSD3/KMT3F, SETD2/KMT3A and ASH1L/KMT2H. NSD1, NSD2, NSD3, ASH1L, and SETD2 are regarded as the predominant H3K36 methyltransferases (136). SETD2 selectively catalyzes H3K36 tri-methylation (H3K36me3), whereas the rest of the H3K36 methyltransferases are responsible for H3K36 mono-methylation or di-methylation (76). On the other hand, there are two de-methyltransferase families of H3K36me: JHDM1/KDM2A/KDM2B and JHDM3/JMJD2/KDM4A-D. JHDM1 and JHDM3 mediate demethylation of H3K36me1/2 and H3K36me2/3, respectively (76,137,138). The reader proteins of H3K36 tri-methylation mainly include LEDGF, MRG15 and SRSF1, with the PWWP (Pro-Trp-Trp-Pro) domain (69).

H3K36me3 is a hallmark of actively transcribed genes and prevents cryptic initiation within gene bodies (139-141). The components of H3K36 methyltransferases with dysregulated expression deeply drive cancer development and progression in cancers (142). H3K36 methylation maintains genome stability through SETD2-mediated mismatch repair, homologous recombination (HR), non-homologous end joining (NHEJ), and replication stress prevention mechanisms in mammalian cells (69). The mutant SETD2 variants appear in enormous solid tumors; SETD2, involving H3K36me3-mediated transcriptional modulation and DNA damage repair, is considered a tumor suppressor (143). SETD2 functions as a tumor suppressor in LUAD, with histone acetylation shown to enhance SETD2’s methylation activity in vitro (144). Oncohistone H3K36M inhibits NSD2, leading to de-repression of retroviral elements, accumulation of double-stranded RNA (dsRNA), and activation of RIG-I/MDA5-mediated immune responses, which depends on SETD2. SETD2 loss abolishes the antitumor immune effect and enhances tumor growth in Kras-Driven Lung Cancer (145). Interestingly, SETD2-mediated H3K36me3 hinders STAT1 from transactivating IL-8 to inhibit tumorigenesis in LUAD (146).

NSD1/2/3 involves various cancer phenotypes [e.g., proliferation, apoptosis, DNA repair, EMT, and cancer metabolism (147)] in a histone methyltransferase activity-dependent manner, whereas they also methylate signaling proteins to modulate tumor oncogenesis (148). The biological contributions of NSD1 in solid tumors and its potential small molecule inhibitors have been reviewed (149). Similarly, it’s feasible to leverage H3K36me inhibitors targeting SETD2/NSDs/SMYD5/ASH1L axis for cancer treatment (142). NSD2-H3K36me2 axis maintains multiple oncogenic pathways in KRAS-driven LUAD models, such as KRAS-MAPK signaling and invasion-promoting matrix metalloproteases: MMP1 and MMP16 (150,151). The gain-of-function mutation of NSD3(T1232A) endows NSD3 with higher catalytic activity for H3K36me2 to promote the mTOR pathway, subsequently accelerating LUSC progression (152). Additionally, KDM4C, abnormally expressed in lung cancer cells, demethylates H3K36me2 at the promoter of T cell recruitment factor CXCL10 to inhibit its expression, causing low CD8+ T cell infiltration and further resistance towards immunotherapy and radiotherapy (153).

H3K79 methylation

H3K79 methylations (H3K79me1/2/3) are catalyzed by DOT1L/KMT4 methyltransferases without the SET structural domain. H3K79me2/3 is found to be enriched in the coding regions of transcriptionally active genes, while H3K79 demethylases remain unclear (76). Meanwhile, Menin, the subunit of H3K4 methyltransferase MLL1/MLL2, may mediate the potential crosstalk between H3K4 and H3K79 methylation (154). H3K79 methylation, recognized by the reader protein Menin, occurs on the globular structural domain of histone H3, not on the histone H3 tail (155).

H3K79me colocalizes and synergizes with H3K36me3 to modulate gene expression (156). DOT1L is associated with extensive biological processes, including cell cycle, DNA damage repair, transcription regulation, acquired drug resistance, and leukemogenesis (157,158). DOT1L has received widespread interest in lung cancer phenotypes (e.g., proliferation, angiogenesis): suppression of DOT1L and H3K79me represses cell proliferation in LUAD (159). Vascular endothelial growth factor (VEGF) is one of the foremost pro-angiogenetic cytokines; LncRNA CAR10 binds with LDHA to promote angiogenesis through the DOT1L/H3K79me3/VEGF axis in LUAD (160,161). Additionally, H3K79me2 drives activation of the RAF/MAPK/ERK signaling axis; accordingly, combined inhibition of DOT1L and the RAF/MAPK/ERK axis yields suppression of tumorigenesis in lung cancer cells carrying the gain-of-function mutation of DOT1L (R231Q) (162-164).

H4K20 methylation

Mono-methylation at lysine 20 of histone H4 (H4K20me1), catalyzed by SETD8 (KMT5A), can be further converted to di- or tri-methylation (H4K20me2/3) by SUV420H1 (KMT5B) and SUV420H2 (KMT5C) (76). PHD8(KDM7B) demethylates H4K20me1, whereas PHF2, KDM4A, and RAD23A/B serve as demethylase for H3K4me2/3 methylation (165). 53BP1 acts as a reader for H4K20me1 and H4K20me2, while ORCA and JMJD2A serve as readers for H4K20me3 (166). The H4K20 methylation, related to transcriptional activation (167) or maintenance of heterochromatin (166), involves a wide range of biological processes (e.g., DNA repair, cell cycle, and genomic integrity) (165,167,168) and tumorigenesis (169).

KMT5A, abnormally overexpressed in tumor tissues, is relevant to prognosis survival in NSCLC (170), maintaining the cancer cell proliferation, migration, invasion and cancer stemness-like phenotype (171). KMT5B expression is lower in various tumors, and it’s also been reported as a tumor suppressor and potential prognostic biomarker in lung cancer (172,173) and colorectal cancer (130). Interestingly, EGFR-mediated H4 phosphorylation recruits KMT5C to facilitate H4K20 methylation, supporting tumor growth in breast cancer (174). H3K40me3, down-regulated in LUSC (67%) and LUAD (28%) patients, influences prognostic survival (173). Loss of KMT5C, an epigenetic factor responsible for H4K20 trimethylation, drives EGFR inhibitors resistance by activating the LINC01510/MET axis, a key bypass mechanism underlying treatment resistance of EGFR inhibitors in NSCLC (175).

The crosstalk between DNA methylation and histone modification

DNA methylation and histone modification (e.g., histone methylation) are not mutually independent; instead, they engage in a series of complex and cooperative crosstalks (176-178). KMT2C, a H3K4 methyltransferase, facilitates SCLC metastasis through decreasing H3K4me1 and H3K4me2 levels in the DNMT3A gene body to downregulate DNMT3A expression, indirectly inducing hypomethylation in pro-metastatic genes: MEIS2 and HOX (179). The presence of H3K4 and H3K36 methylation hinders DMNT3 from recognizing and catalyzing DNA methylation (177); UHRF1 promotes DNA methylation through recognizing and locating with H3K9me3 sites, thereby recruiting DNMT1 (180). The ubiquitination of H2A at lysine 119 causes NSD3 activity loss (181).

H3K27me3 and H3K36me2/3 are mutually exclusive in the same histone, while H3K36me2/3 cooperates with DNMT3A/3B to maintain transcriptional silencing (136,139). Polycomb PHF19 mediates the transformation of H3K36me3 to H3K27me3 (182). Histone acetylation, recognized by BRD4, recruits complex RNF20/RNF40/WAC for H2B K120 ubiquitination, which stimulates DOT1L-mediated H3K79me3 (183).

Histone acetylation

Histone acetylation at lysine sites enhances chromatin openness by disrupting the charge interaction between lysine and DNA, a modification typically associated with permissive gene transcription (184). Histone acetylation and deacetylation are modulated by two different enzyme families: the lysine acetyltransferases (KATs)/histone acetyltransferase (HATs) and histone lysine deacetylases (HDACs), respectively. The three components of HATs families are the GCN5-related N-acetyltransferase family (GNAT), MYST (Moz, Ybf2/Sas3, Sas2, Tip60), and p300/CBP (protein of 300 kDa and CREB-binding protein). The representatives of GNAT are GCN5 and PCAF (185), which are important subunits of the Ada-two-A-containing (ATAC) complex that acetylates histone at H3K9 and H3K14 (186,187). MYST family, associating with tumorigenesis (188), is composed of KAT8 (MYST1/MOF), KAT7(MYST2/HBO1), KAT6A(MYST3/MOZ), KAT6B(MYST4/MORF), and TIP60/KAT5 (189,190). According to their sequence homology with yeast deacetylases, histone deacetylases are categorized into four major classes: Class I (HDAC1/2/3/8), Class II (IIa: HDAC4/5/7/9, IIb: HDAC6/10), Class III (SIRT proteins), and Class IV (HDAC11). Class III members depend on nicotinamide adenine dinucleotide (NAD) as a cofactor, whereas the other HDACs primarily rely on zinc ions (191). The histone acetylation reader proteins include bromodomain-containing protein 4 (BRD4) and transcription initiation factor TFIID subunit 1 (TAF1) (192).

Although there are thirteen types of histone acetylation observed in a wide range of carcinomas, they play distinct roles in cancer progression. The pro-tumoral histone acetylation consists of H3K4ac, H3K9ac, H3K14ac, H3K18ac, H3K23ac, H3K27ac, while the anti-tumoral histone acetylation includes H3K4ac, H3K14ac, H3K18ac, H3K23ac, H3K56ac (193). Furthermore, these H3 acetylation (H3K9ac, H3K18ac, H3K23ac, H3K27ac, H3K56ac) are regarded as potential cancer biomarkers in lung cancer (193). Here, we provide a concise summary of representative research on histone acetylation in lung cancer (Figure 3).

ARID1A, which harbors loss-of-function and missense mutations in 7.5% of lung cancer patients, facilitates glycolysis by reducing the location of HDAC1 and maintaining the acetylation of histone-4 lysine (H4Kac) in the promoter of glycolytic genes (PGAM1, PKM, and PGK1) (194,195). YEATS2, as an H3K27ac reader, preserves ATAC-mediated H3K9ac through recruiting and stabilizing ATAC complex, supporting essential gene expression in NSCLC (196). KAT7 (HBO1) augments NSCLC progression (proliferation, migration, and apoptotic resistance) via activating the histone acetylation/CCR2/MYLK/VEGFR2/OCIAD2 axis (197). Besides, p300 enhances oncogenic signaling MYC and NF-κB/IL6 expression to maintain proliferation, cell cycle, and metastasis in lung cancer (198-200). Silencing of SETD2 accelerates KRAS-driven lung cancer through enhancing oncogenic genes (KRAS signatures and PRC2 targets) with H3K27ac-dependent and chromatin accessibility-dependent (201).

H3K27ac serves as a critical bridge connecting tumor epigenetic dysregulation and tumor immune evasion. For instance, the level of H3K27ac on IFNγ-stimulated genes is reduced, which leads to insensitivity of tumor cells to the cytotoxic factors released by T cells in ICB resistance of lung cancer (202). Interestingly, HDAC2/histone acetylation/SP1 signaling axis maintains the pro-tumor M2-like phenotype of tumor-associated macrophages, facilitating tumor growth and angiogenesis in lung cancer (203). HDAC3 deacetylates H3K9ac to suppress NKG2DL transcription, thereby inhibiting the recognition of NK cells and CD8+ T cells to tumor cells in SCLC (204). KAT6A/B inhibitors (205), CBP/p300 inhibitors, and CBP/p300 bromodomain inhibitors, are thought to be promising novel anticancer strategies (206).

Histone lactylation

As a novel type of histone modification at lysine, the histone lactylation was first discovered and identified in 2019 (207). Histone lactylation is catalyzed by the writer CBP/p300 (207), GCN5 (208), and HBO1(H3K9la, histone H3 lysine 9 lactylation) (209), using lactyl-CoA derived from lactate. In contrast, HDAC1-3 and SIRT1-3 (sirtuins) are identified as the erasers of histone lactylation (210). While the BRG1 protein was confirmed as the first histone H3 lysine 18 lactylation (H3K18la) reader (211), other potential readers are still poorly understood (212). There are five residues reported to be lactylated in histone proteins: H3K9, H3K14, H3K18, H3K56, and H4K12 (213). Connecting lactate metabolism (even glycolysis) to epigenetic modifications (214), histone lactylation promotes open chromatin and subsequently transcriptional activation. This process is involved in tumorigenesis (215,216) and the reshaping of tumor microenvironment (TME) through modulating cGAS-STING, TLR, RIG-I signaling pathway (212,217-219).

The role of histone lactylation in lung cancer is summarized as follows (Figure 4). The lactate dehydrogenase-A (LDHA) catalyzes the conversion of pyruvate to lactate in the glycolysis pathway (220). AKR1B10 upregulates LDHA/glycolysis/lactate axis to enhance H4K12la/CCNB1 axis in pemetrexed-resistant lung cancer (221). The anti-tumoral role of LKB1 involves downregulation of the lactate/histone H4 lactylation/SP1 axis in LUAD (222). Numb/Parkin axis drives neuroendocrine trans-differentiation via promoting glycolysis/lactate/H3K18la/neuroendocrine-associated genes (MYCN, ACSL2) signaling axis in prostate and lung cancer (223). Likewise, BZW2 facilitates tumor progression through glycolysis/lactate/H3K18la/IDH3G axis in LUAD (224). NCAPD3 and TOP2A promote NSCLC progression through enhancing the LDHA/lactate/H3K18la axis in NSCLC (225,226). Interestingly, histone lactylation-driven YTHDF2 forms a feedback loop: YTHFD2 maintains SFRP2 stability to enhance glycolysis/lactate/H3K18la axis (227). Moreover, AIM2, elevated by glycolysis/lactate/histone lactylation axis, maintains the activation of STAT5B/ACSL4 to protect lung cancer from ferroptosis in lung cancer (228).

Figure 4 Histone lactylation in lung cancer tumor cells. The molecular mechanisms of histone lactylation (left) and it’s biological roles in lung cancer (right).

Histone lactylation reshapes lung cancer TME. The glycolysis/H3K18la/NF-κB/TNFR2 axis derives the immunosuppressive effects of regulatory T cells. Combining AZD3965 (lactate transporter inhibitor) or Oxamate (lactate dehydrogenase inhibitor) with PD-1 blockade is more effective than PD-1 blockade therapy alone (229,230). MCT1 maintains mitochondrial hemostasis through promoting lactate/H3K18la/ferridoxin reductase (FDXR) axis; MCT1 inhibition enhances ICB efficacy (231). H3K18 lactylation drives POM121 expression, which potentiates PD-L1-mediated immune evasion by stabilizing MYC to maintain the MYC/CD274 axis (232). A positive feedback loop exists in lung cancer tumor microenvironment: CTHRC1+ cancer associated fibroblasts (CAFs) release CTHRC1 to promote cancer cell lactate accumulation through TGFBR2/TGF-β/Smad3/glycolysis axis; these lactate in turns enhance H3K18la to upregulate CTHRC1 in CAFs, involving EGFR-TKI resistance (233). NDRG1 promotes glycolysis and lactate accumulation through inhibiting the ubiquitination of LDHA; these lactates reprogram macrophage to immunosuppressive phenotype in a H3K18 lactylation dependent manner (234). While lactylation plays a crucial role in the macrophage-mediated lung disease (e.g., pneumonia and lung cancer) (235), we anticipate further investigation into how histone lactylation reshapes TME and its clinical implications in precision medicine.

2-deoxyglucose (2-DG), glycolytic enzyme HK2 inhibitor, suppresses cancer cell proliferation and tumor growth in KRAS-mutated lung cancer (236). Additionally, it represses LKB1/AMPK/ERK pathway in KRAS wild-type NSCLC cells (237). Another study finds that 2-DG not only induces proliferation inhibition and glycolysis suppression, but also attenuates immunosuppressive TME through reducing pro-tumoral MDSCs infiltration (238). Oxamate (LDHA inhibitor) induces proliferation inhibition, cell cycle arrest at G0/G1, apoptosis, and ROS accumulation , contributing to its anti-tumor properties in NSCLC cells (239). By perturbing lactate metabolism, the monocarboxylate transporters (MCT) inhibitor AZD3965 shows significant potential against various types of cancer in preclinical stage (240), including SCLC (241). The activation of H3K18la/Nur77 signaling axis leads to antigen recognition and inhibition of anti-tumor activity. Lactate inhibition reduces the expression of Nur77 and restore T cell function to enhance the therapeutic effect of PD-1 blockade in SCLC (242). Shikonin, a natural product that targets PKM2 (pyruvate kinase M, glycolytic enzyme), attenuates glycolytic and lactylation effect and collaborates with PD-1 blockade therapy (228). Additionally, natural product fargesin decreases histone lactylation in NSCLC models via downregulating PKM2/glycolysis/lactate axis (243). Moreover, leveraging natural compounds with LDH inhibitory activity and immune-modulating properties for cancer treatment is considered a promising alternative strategy (161,244). Therefore, it’s helpful to mine potential histone lactylation inhibitors from natural product libraries.

The 327 lactylation-related genes (LRGs) are utilized for generating a prognostic model that includes an oncogene, KRT81, which is highly expressed in LUAD (245). Similarly, another research constructs a prognostic model with nine LRGs (246). SLC2A1, a potential prognostic biomarker, shows a strong correlation with lactylation score in LUSC (247). However, the aforementioned studies for predicting patient prognosis lack additional experimental evidence supporting the glycolysis/histone lactylation axis. These lactylation-associated prognostic models still lack validation in independent external clinical cohorts, and further clinical investigations are urgently needed to verify their translational applicability. Composed of five the solute carrier (SLC) family genes, a prognostic model is relevant to lactylation modification. Further experiments demonstrate that silencing SLC25A9 promotes LUAD progression through upregulating histone lactylation (248). Although the crosstalk between metabolic reprogramming and epigenetic reprogramming is beyond the scope of our discussion (249), it is nonetheless significant. There appears to be a lack of research on the integration of metabolomes and epigenomes for lung cancer precisive oncology.

Epigenetic biomarkers in lung cancer

Non-invasive biomarker detections, including liquid biopsies based on microRNA and free DNA (cfDNA), have the potential to reduce barriers to screening and thus reduce lung cancer mortality (2). In vitro diagnosis (IVD) utilizing the DNA methylation biomarkers have been applied for early diagnosis in lung cancer, such as, the commercial Cervi-M^® and Oral-M^® DNA assays (iStat Biomedical Co.) (250). However, the potential for stratified therapy based on DNA methylation detection, as well as the importance of other epigenetic biomarkers (i.e., miRNAs and histone modifications) in diagnosis and treatment, remains unclear. Further discussion of the aforementioned topics enhances our understanding of epigenetic precision medicine. Several liquid biopsy biomarkers based on DNA methylation have been approved by the Food and Drug Administration (FDA) for screening and early detection in solid tumors (251).

Methylation for lung cancer prognosis and stratified treatment

Liquid biopsies, have aroused significant interest among researchers in recent decades, which may serve as a promising adjunct to precision medicine by profiling patient methylation patterns. Liquid biopsy technology, which monitors circulating tumor-associated biomarkers, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EV), circulating RNA and proteins, offers non-invasive or less invasive options for early diagnosis, stratified treatment, and prognosis monitoring for cancer patients. However, this technology is still under development for realizing precision medicine in cancer management (252). The methylation level of cfDNA derived from liquid biopsy can be used not only for lung cancer screening and diagnosis, but also for real-time monitoring of primary and metastatic cancer status, reflecting tumor dynamics and patients heterogeneity in a small-scale clinical cohort (253). The significant role of cfDNA methylation in lung cancer management has been reviewed elsewhere, covering laboratory methods, clinical availability, and application challenges (254,255). Moreover, via confocal 3D imaging for DNA methylation staining and analysis, global DNA hypomethylation can effectively discriminate lung cancer cells from normal counterparts. This molecular signature allows the identification of hypomethylated cancer cells in both patient sputum and tumor tissues, showing great potential as a non-invasive alternative for lung cancer screening (41).

The elevated blood DNA methylation levels are significantly associated with increased lung cancer risk, supporting the potential of DNA methylation signatures as epigenetic biomarkers for identifying highrisk individuals for lung cancer screening (256). DNA methylation biomarkers for the early diagnosis of lung cancer include RASSF1A, SHOX2, PTGER4, HOXA9, and p16(INK4a) (35,257-259). Recently, clinical subtyping is profiled using DNA methylation detected by plasma liquid biopsy, demonstrating differential DNA methylation patterns across four SCLC subtypes (260). The four gene methylation levels (SOX17, CDO1, TAC1, and HOXA7), simultaneously detected by the digital methylation-specific PCR method from liquid biopsies of peripheral blood, have been investigated for early screening of NSCLC in clinical studies (261). The malignancy level of the lung cancer tumor microenvironment can be quantified by the DNA methylation of fibroblasts, and this fibroblastrelated methylation index is also related to patient prognosis (262). The methylation of SHOX2 is detected at higher level in lung cancer patients than that of healthy peoples, and may serve as a potential diagnostic biomarker (263). Methylation of SHOX2 and PTGER4 in plasma samples can effectively distinguish between lung cancer and non-malignant lung diseases (264). A ten-gene DNA methylation signature has been developed for predicting anti-VEGF therapy (bevacizumab) response in NSCLC (265).

EZH2 activation is positively implicated in the NE transformation from LUAD to SCLC, while the hypomethylation of key driver for NE differentiation, WNT signaling, cell stemness, and EMT, has been observed (266). The mutated status of H3K79 methyltransferase DOT1L (missense mutations or frameshift variants versus wildtype) may serve as a potential biomarker for predicting ICI response in NSCLC (267). The combined detection of ctDNA and nucleosome H3K27me3 level enhances accuracy compared to the single ctDNA method in plasma samples in France NSCLC cohorts, showing translational potential in non-invasive MRD monitoring and stratified treatment (268). The KMT2C methylation in plasma cfDNA has been regarded as a potential non-invasive circulating epigenetic biomarker to predict prognosis of NSCLC patients (269). The DNA methylation levels at KDM2A (cg11637544) and KDM1A (cg26662347) sites are associated with unfavorable prognosis of NSCLC patients (270).

In bioinformatical analyses, numerous prognostic scoring models are developed for predicting patients’ prognosis and stratified treatment response based on methylation regulators (271-273). However, these models lack further validation to delineate the model’s clinical feasibility in independent cohorts. Multiple clinical trials are under recruitment based on the detection of DNA methylation in blood plasma for lung cancer screening and early diagnosis Additionally, combinational strategies between cfDNA detection and other approaches (PET-CT, AI analysis) are also highly anticipated (Table S1). Nevertheless, the clinical feasibility of ctDNA analysis as a screening tool for the detection of early NSCLC requires further investigation, and its combination with other tests for blood biopsy may improve diagnostic sensitivity (274).

Epigenetic biomarkers in immunotherapy

The clinical trials joining epigenetic drugs (DNMT, LSD1, and HDAC inhibitors) with checkpoint inhibitors: PD-1/PD-L1/CTLA-4 blockers (Nivolumab, Pembrolizumab; Durvalumab; Tremelimumab) have finished or are undergoing in lung cancer (29). HDAC inhibitor Romidepsin enhanced PD-1 blockade response through up-regulating T-cell recruitment chemokines in LUAD preclinical models (275). DNA methylation heterogeneity exists in NSCLC patients received immunotherapy, which may help predict clinical benefit to immunotherapy, although the underlying mechanisms remain poorly understood (276). Similarly, the differential methylation of CYTIP and TNFSF8 is able to serve as a potential biomarker for predicting immunotherapy response in NSCLC (277). The global reduction of genomic methylation in promoter regions is positively correlated with immune therapy resistance in lung cancer (278).

In a multi-center cohort of 142 advanced NSCLC patients treated with PD-1 blockade (nivolumab or pembrolizumab), the DNA methylation signature: EPIMMUNE and unmethylation of FOXP1 are significantly associated with elevated survival lifespan and better immunotherapy response (279). Similarly, the enhancer demethylation signature has been explored for prognostic stratification and prediction of immune therapy resistance in clear-cell renal cell carcinomas (280). The clinical trial (NCT04566432), recruiting 83 NSCLC patients who received ICI therapy, develops a multimodal model for predicting therapy response, with the collection of ctDNA and radiography data (281). The multi-Omics model (clinic-RadmC), generated by multimodal data (clinical information, cfDNA data, and radiomics), shows superior potential for distinguishing indeterminate pulmonary nodules (IPLs) and lung cancer (282). Recently, based on the blood-based genomic immune subtypes (bGIS) model integrating blood ctDNA profiling, advanced NSCLC patients are stratified into three subtypes: bGIS-1, bGIS-2, and bGIS-3. The bGIS-1 cohort with ctDNA-negative status has the best survival benefit, while the chemotherapy plus PD-1 inhibitor is strongly recommended for bGIS-2 treatment, and the bGIS-3 subgroup has no priority in using PD-1 inhibitor (283). In short, epigenetic regulators and epigenetic signatures, with DNA methylation as a typical representative, may serve as promising biomarkers for immunotherapy and combined therapy; however, their molecular mechanisms in immunotherapy resistance are poorly understood in lung cancer. In addition, there seems to be a lack of research on epigenetic biomarkers in precision medicine for lung cancer radiotherapy (284).

Epigenetic strategy for lung cancer treatment: an update

Epigenetic treatment drugs (Epi-drugs), including DNMT inhibitors, HDAC inhibitors, BET inhibitors, EZH2 inhibitors, LSD1 inhibitors, and NSD2 inhibitor (KTX-1001), have been reported to be effective in preclinical or clinical trials (47,285). Several clinical trials are currently in progress to investigate the availability of treatments targeting epigenetic modulators in SCLC, including EZH2 (DS-3201b), LSD1 (GSK2879552), and HDAC (LBH581) (286). Another early study summarizes that the epigenetic drugs involved in clinical trials for SCLC, including HDAC inhibitors, LSD1/KDM1A inhibitors, and PARP inhibitors (47).

The combination of epigenetic drugs with immune checkpoint blockade and/or chemotherapy provides promising alternatives for cancer treatment (47,287). The effectiveness of combining HDAC inhibitors with anti-PD-1 antibody has been demonstrated in early clinical trials (288). Unfortunately, while combined regimens of DNMT inhibitors with chemotherapy or immunotherapy show superior efficacy relative to single-agent therapy, their translational potential for lung cancer treatment is still limited (289). Several small molecules targeting epigenetic modulators are currently undergoing clinical trials (285), which may provide potential epigenetic therapies for lung cancer treatment (Figure 5, Table 3).

Figure 5 The schematic diagram of potential epigenetic drugs against lung cancers. H3, histone H3; HDAC, histone lysine deacetylase; K, lysine.

KMT or KDM inhibitors

Mutational deficiency of KMT2D reduces RPTP expression in an epigenetic reprogramming-dependent manner, which activates oncogenic RTK-RAS signaling to promote tumorigenesis in LUSC (290). This implies that patients with RAS mutations in LUSC can be further stratified for treatment based on KMT2D mutation status. A series of KDM4 small molecule inhibitors were developed against various cancers in preclinical (291). Among them, the modified 8-hydroxyquinoline CCT1 significantly inhibits lung cancer cell proliferation (292). KDM5A promotes the neuroendocrine differentiation in SCLC through inhibiting the NOTCH pathway to maintain ASCL1 expression (293). The KDM5A inhibitor Ryuvidine relieves gefitinib resistance in SCLC cell lines (294), while KDM5A also was reported to maintain gefitinib resistance and paclitaxel resistance in LUAD cells (295,296). Another preclinical study suggests that KDM6A inhibitors are potential targeting agents for KMT2C-CD mutant patients (297). However, further observations are needed to determine whether KMT and bromodomain and extraterminal domain (BET) proteins are promising targets for the diagnosis and treatment of lung cancer (298,299). Meanwhile, SETDB1 inhibitors, which perform anti-tumor activity via hindering SETDB1-mediated H3K9 methylation and inducing tumor cell apoptosis, are under development (108). The clinical trial (NCT04606446) of KAT6A/B inhibitors is currently underway for metastatic NSCLC patients (205).

HDAC inhibitors

HDAC inhibitors, when combined with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitors (PFI-1), attenuate TGF-β1-induced PD-L1 expression and EMT transition in NSCLC cell lines (183). HDAC inhibitors are thought to as a potential and promising pharmacotherapeutic strategy against metastatic lung cancer, particularly in combination with ICB therapy. This combination of vorinostat (pan-HDAC inhibitor) and pembrolizumab (anti-PD1 agent) was well tolerated with a disease control rate of 67%, and exerted promising preliminary antitumor efficacy even in patients with advanced or metastatic lung cancer who had previously failed immunotherapy (300). The combination of belinostat (Beleodaq, PXD101, pan-HDAC inhibitor) with standard chemotherapy (cisplatin and etoposide) achieves an average objective response rate of 43% in advanced SCLC and other neuroendocrine tumors. Encouragingly, marked tumor regression can still be observed in patients with disease progression following prior standard chemotherapy, and most patients are well tolerant to multiple treatment cycles (301). Moreover, several HDAC inhibitors suppress SCLC metastasis through suppressing the RCOR-HDAC complex to activate YAP transcription (302). The natural product celastrol augments histone acetylation and, in combination with the HDAC inhibitor (Entinostat) to suppress tumor growth in lung cancer (303).

EZH2 inhibitors

EZH2 inhibition (Tazemetostat) represents a novel cancer therapeutic approach, with promising clinical progress reported across diverse malignancies, including SCLC (287). EZH2 inhibition causes enhanced T-cell regulated antitumor immunity and antigen presentation, which enhances ICB response and overcomes acquired resistance to ICB in preclinical models of prostate and head and neck cancer (304). Recently, while a clinical trial identifies the primary efficiency of the combined therapy (EZH1/2 inhibitor: Valemetostat and chemotherapeutic agent: Irinotecan); however, the adverse event rate is up to 20% in recurrent SCLC patients (305). In the SCLC model, EZH2 inhibitors restore T cell-mediated killing against cancer cells and increase the expression of antigen-presenting MHC class I (MHC-I) (306,307). Within tumor microenvironment, EZH2-mediated H3K27me3 leads to transcriptional silencing of MHC-I and CCL2, inhibiting CD8+ T cell recognition and recruitment of macrophage, respectively (308). EZH2 inhibitors partially overcome chemoresistance in SCLC by decreasing EZH2-mediated H3K27me3 towards SLFN11 (309). Meanwhile, inhibiting EZH2 can disrupt neuroendocrine phenotypes and upregulate DNA damage-related genes in lung cancer (306,307). The inhibition of EZH2 enhances sensitivity to chemotherapy in preclinical model of lung cancer (310,311). Further clinical evidence is required to elaborate the potential of EZH2 in combination therapy for lung cancer, as well as the heterogeneity of therapeutic sensitivity across different lung cancer subtypes.

LSD1 inhibitors

LSD1 inhibitor ORY-1001 represses tumorigenesis and ACSL1-mediated neuroendocrine transition through activating NOTCH pathway in SCLC preclinical models (312,313). ORY-1001 also impairs glycolysis through repressing LSD1/hexokinase-II(HK2) singling axis in lung cancer cells (314). Another LSD1 inhibitor T-3775440 disrupts the interaction between LSD1 and the transcriptional repressor INSM1, which suppresses the expression of neuroendocrine genes (e.g., ASCL1) and SCLC cell proliferation (315).The combination of LSD1 inhibitors with anti-PD-1 antibodies promotes antigen presentation through upregulation of MHC-I, thus enhancing CD8+ T cell-mediated anti-tumor immunity (316). Unfortunately, LSD1 inhibitor GSK2879552 has failed to confer clinical benefits in the phase I trial involving SCLC: poor clinical efficacy and considerable adverse reactions (317,318). Combination therapy with other therapeutic regimens and the development of novel non-covalent LSD1 inhibitors may overcome these limitations and improve the clinical translational potential of LSD1-targeted therapy. Nevertheless, its therapeutic potential in other lung cancer subtypes remains worthy of further exploration.

Conclusions

We depict epigenetics and its application potential in lung cancer precision medicine through highlighting the importance of DNA methylation, histone modifications, and further therapeutic implications. While previous studies have delineated the role of DNA methylation in the pathogenesis, diagnosis and prognosis, and treatment of lung cancer (35), we underline the differences in epigenetic dysregulation of histone modifications, methylation-related biomarkers for current therapies, and the latest precision treatment concepts. In the foreseeable future, precision oncology for lung cancer deeply integrates with artificial intelligence and multi-omics to accelerate personalized treatment and empower clinical decision making (319). The advancement of high-throughput sequencing (i.e., single-cell transcriptomics and spatial transcriptomics) offers high-dimensional data that provides valuable insights into tumor biology and tumor microenvironment, enhancing our understanding of lung cancer precision medicine. We also anticipate further explorations on chromatin remodeling regulators for lung cancer targeted therapy, focusing on SWI/SNF components (i.e., BCL7A, SMARCB1) and PRC family: PRC1 components (i.e., CBX2, PCGF1-6) and PRC2 components (i.e., JARID2, ASXL1-3) (29,320). The approval of epigenetic drugs has accelerated the progress of precision medicine in lung cancer, and we look forward to further stratification and personalized treatment based on epigenetic profiles derived from patient-sourced samples (tumor biopsy tissue, blood, etc.), particularly focusing on histone modifications (Figure 6).

Figure 6 The schematic diagram of epigenetic precision medicine in lung cancers. Epigenetic profiling paves the way for early diagnosis, stratified treatment and prognostic assessment in lung cancer.

Extensive molecular profiling studies have been performed across a broad spectrum of diseases, both malignant and nonmalignant. Maximizing the exploration of multiple omics data and selecting the best omics datasets for modeling are beneficial for the implementation of precision medicine and avoiding duplicate academic investments. Additionally, there are several potential obstacles in precision medicine projects, which include the following: (I) diversity and representativeness of datasets: several high-throughput sequencing data or genomic studies (such as single-cell sequencing and spatial transcriptomics) are single-center, small-scale, and focus primarily on specific ethnic cohorts (overlooking rare subtypes and ethnical genomic mutations) (321). Such unrepresentative data may create a disconnect between the model and the actual application population (i.e., external validity) (17). This problem can be addressed through cross-cohort aggregation that integrates large-scale sequencing and genomics datasets (322), such as the Human Cell Atlas project (323). (II) Biomarkers for stratified treatment: given the heterogeneity and dynamics shifts (phenotype transformation, acquired resistance, etc.) in cancer patients exist, it is crucial to focus on the significant role of biomarkers in predicting treatment outcomes of stratified interventions. This perspective can be enhanced through liquid biopsy and functional precision medicine models: microfluidic chip, tumor organoids, PDX, patient-derived cell (PDC) cultures (11). (III) Clinical trial design and economic accessibility: These are also critical factors that cannot be overlooked, as they significantly limit the development of precision medicine (17,324-326). However, establishing a standard sample processing process and precision medicine research framework tailored to an institution’s needs requires significant investment in both economy and intelligence (327).

Epigenetic drugs targeting DNA methyltransferase, histone deacetylase, EZH2 and LSD1 exert prominent anti-tumor effects against lung cancer. Combination therapy with chemotherapy, targeted agents and immune checkpoint inhibitors can synergistically strengthen anti-tumor immunity and improve treatment insensitivity. Nevertheless, current epigenetic therapies still have drawbacks including limited therapeutic efficacy, obvious adverse effects and activation of compensatory pathways. Future research will focus on developing novel inhibitors with high selectivity and low toxicity, and exploring candidate drugs derived from natural products. Optimized combination regimens will be adopted to maximize clinical benefits. Elucidating the crosstalk of epigenetic modifications and regulatory mechanisms of tumor microenvironment contributes to discovering innovative therapeutic targets and strategies. Combined application of epigenetic biomarkers and liquid biopsy facilitates stratified and individualized medication for lung cancer. The advancement of clinical trials supported by multi-omics technologies will further accelerate the clinical translation of epigenetic therapy in lung cancer management. Given that we have chosen only representative references, this review may fail to collect a substantial number of literatures. While the role of post-translational modifications (such as methylation and lactylation) is not within the scope of this review, their potential impact on lung cancer precision oncology is emerging and cannot be overlooked.

In conclusion, regulating epigenetic progresses and targeting epigenetic modulators with small molecule inhibitors are theoretically feasible for lung cancer alternative and second-line treatment. Epigenetic characteristics, such as DNA methylation and histone modification, may augment precision medicine in lung cancer by improving diagnosis and treatment stratification.

Acknowledgments

All figures were created with BioRender (https://www.biorender.com/).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0324/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0324/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82273161), the National Key Research and Development Program of China (No. 2022YFA1303200), Natural Science Foundation of Sichuan Province (grant No. 2024NSFSC1873 to G.M.), and Postdoctor Research Fund of West China Hospital, Sichuan University (grant No. 2024HXBH103 to G.M.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0324/coif). G.M. reports that he received grants from Natural Science Foundation of Sichuan Province (No. 2024NSFSC1873) and Postdoctor Research Fund of West China Hospital, Sichuan University (No. 2024HXBH103). G.Y. reports that he received grants from National Natural Science Foundation of China (No. 82273161) and the National Key Research and Development Program of China (No. 2022YFA1303200). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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