The role and mechanism of METTL3 in cancer: emerging insights into m6A methylation and therapeutic potential

Abstract

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, plays a crucial role in regulating RNA metabolism and gene expression. Among m6A regulators, METTL3 functions as the catalytic core of the m6A methyltransferase complex and has emerged as a critical epitranscriptomic modulator in cancer. An expanding body of evidence demonstrates that METTL3 is aberrantly expressed in various malignancies, contributing to tumor progression, metastasis, stemness, immune evasion, and resistance to chemotherapy and targeted therapies. Nonetheless, its role remains highly context-dependent, exerting either oncogenic or tumor-suppressive effects based on cancer type and the microenvironment. This review offers an in-depth analysis of the molecular structure and biological functions of METTL3, summarizes its expression profiles and prognostic significance in major human cancers, and examines the mechanisms through which METTL3 modulates tumor biology. In addition, current advancements in the therapeutic targeting of METTL3 are discussed, including small-molecule inhibitors, such as STM2457, their preclinical efficacy, and the challenges and future prospects for clinical translation.

Introduction

Cancer continues to rank as a primary cause of death globally, with rising incidence and mortality rates constituting a major public health concern [1–3]. Despite significant progress in molecular diagnostics and targeted therapies, numerous tumors exhibit considerable heterogeneity, resistance to treatment, and recurrence [4–6]. These issues emphasize the pressing necessity of identifying novel regulatory mechanisms that govern tumorigenesis and therapeutic response [7]. In recent years, alterations in epigenetics and epitranscriptomics have gained recognition as key regulatory factors in cancer, further complicating the control of gene expression beyond alterations in DNA sequence [8, 9].

Epitranscriptomic regulation, particularly N6-methyladenosine (m6A) methylation, represents a fundamental layer of post-transcriptional gene regulation in eukaryotic cells [10–12]. m6A modifications are enriched near stop codons, 3′ untranslated regions (UTRs), and long internal exons of messenger RNAs (mRNAs) [13, 14]. As the most abundant internal modification on eukaryotic mRNA, m6A plays a significant role in RNA metabolism regulation, influencing splicing, export, stability, and translation [15]. The biological functions of m6A depend on the coordination of a network of regulatory proteins [16–18]. “Writers” such as METTL3, METTL14, and WTAP form the core methyltransferase complex that installs m6A marks on target mRNAs. These modifications are reversible, with “erasers” such as FTO and ALKBH5 capable of removing them, enabling dynamic regulation in response to cellular signals. “Readers”, including members of the YTH domain and IGF2BP families, recognize m6A-modified transcripts, mediating various downstream effects, such as altered mRNA stability, translation efficiency, nuclear export, and splicing. As a dynamic and reversible epitranscriptomic modification, m6A governs cellular fate, differentiation, immune responses, and tumorigenesis [19, 20].

Among the m6A methylation regulators, METTL3 functions as the central catalytic subunit of the m6A “writer” complex [13, 21–23]. It forms a stable heterodimer with METTL14, which facilitates RNA substrate recognition and stabilizes the complex [24, 25]. In addition, METTL3 interacts with auxiliary factors, such as WTAP, VIRMA, RBM15, and ZC3H13, directing its nuclear localization and ensuring specificity [26]. METTL3 has attracted significant attention in cancer research due to its altered expression and diverse functional roles. Elevated levels of METTL3 have been reported in various solid tumors, including lung, liver, colorectal, and gastric cancers, often correlating with enhanced proliferation, metastasis, stemness, and chemotherapy resistance. However, its biological role is not universally oncogenic. In certain cancers, such as papillary thyroid carcinoma and specific subtypes of non-small cell lung cancer, METTL3 appears to exert tumor-suppressive effects, indicating a context-dependent functional divergence influenced by cell type and the microenvironment. This duality complicates its potential as a clinical target, highlighting the importance of precise characterization of METTL3 activity within specific tumor types. This review offers a comprehensive examination of METTL3 in cancer, including its molecular mechanisms, context-dependent expression, effects on tumor behavior, therapeutic strategies, and future prospects for clinical application.

Overview of m6A RNA methylation and METTL3

The m6A modification landscape

m6A is the predominant internal RNA modification in eukaryotic mRNA, representing over 80% of all methylated ribonucleotides [27, 28]. This modification is dynamic and reversible, playing a key role in the post-transcriptional regulation of gene expression. It primarily occurs at the consensus motif RRACH (R = A/G, H = A/C/U), with a notable enrichment near the 3′ untranslated region (3′UTR), stop codon, and extended internal exons of mRNA transcripts [29]. The m6A regulatory machinery comprises three essential components: writers (methyltransferases), erasers (demethylases), and readers (m6A-binding proteins) (Fig. 1). The primary m6A methyltransferase complex includes METTL3 (the catalytic subunit), METTL14 (structural support), WTAP (localization scaffold), and regulatory cofactors, such as VIRMA, RBM15, and ZC3H13 [24, 30, 31]. Demethylation is facilitated by FTO and ALKBH5, while m6A readers, including YTHDF1/2/3, YTHDC1/2, and IGF2BP1/2/3, interpret methylation marks to regulate RNA stability, splicing, translation, and localization [17, 32, 33]. Functionally, m6A methylation is essential for processes, such as development, cell fate transitions, stress responses, circadian rhythm, and cancer. Alterations in m6A regulators are frequently observed across various malignancies, impacting tumorigenesis, stem cell properties, immune evasion, and resistance to therapy [34–36].

Fig. 1.

METTL3 functions as the catalytic hub of the m6A methylation and exerts tumor-type-specific roles. METTL3 forms the catalytic core of the m6A writer complex via a stable heterodimer with METTL14, assisted by cofactors (e.g., WTAP, RBM15, ZC3H13, and METTL16) to refine substrate specificity and localization. m6A marks are reversibly regulated by demethylases (FTO, ALKBH5, ALKBH3) and read by effector proteins (YTH family, IGF2BPs, HNRNPs), shaping RNA metabolism. METTL3 exhibits context-dependent functions, acting as an oncogene in LUAD, HCC, GC, PCa, CRC, glioma, RCC, and BCa, but playing tumor-suppressive roles in non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC)

METTL3 expression and functional roles in cancer

Dysregulation of METTL3, a core component of the m6A RNA methyltransferase complex, is increasingly reported across a wide array of malignancies (Table 1). Its expression is closely associated with tumor stage, metastatic behavior, therapeutic resistance, and patient prognosis, but exhibits context- and subtype-dependent variability.

Table 1.

METTL3 expression and clinical significance in human cancers

Tumor type	METTL3	Expression	Clinical feature	Refs.
Gastric cancer	METTL3	Upregulation	TNM stage, lymph node metastasis, and overall survival	[37]
	METTL3	Upregulation	TNM stage, vessel invasion, and overall survival	[38]
	METTL3	Upregulation	Overall survival	[39]
	METTL3	Upregulation	Progression-free survival, overall survival, and post-progression survival	[40]
Colorectal cancer	METTL3	Upregulation	Metastasis	[41]
	METTL3	Upregulation	Overall survival	[42]
	METTL3	Upregulation	Metastasis, overall survival, and disease-free survival	[43]
	METTL3	Upregulation	Lymph node invasion, distant metastasis, and overall survival	[44]
Liver cancer	METTL3	Upregulation	Overall survival, and disease-free survival	[45]
	METTL3	Upregulation	Drug resistance, and overall survival	[46]
	METTL3	Upregulation	Pathological stage, TNM stage, lymph node metastasis, and overall survival	[47]
Pancreatic cancer	METTL3	Upregulation	Overall survival	[48]
	METTL3	Upregulation	Age, TNM stage, pathological stage, and overall survival	[49]
	METTL3	Upregulation	Pathological stage, and N stage	[50]
	METTL3	Upregulation	Drug resistance to gemcitabine	[51]
Lung cancer	METTL3	Upregulation	Overall survival, and drug resistance	[52]
	METTL3	Upregulation	Overall survival, and drug resistance	[53]
	METTL3	Downregulation		[54]
	METTL3	Upregulation	Diagnostic biomarker, and overall survival	[55]
	METTL3	Upregulation	Tumor differentiation, advanced stage, and increased metastasis, and overall survival	[56]
Glioma	METTL3	Upregulation	Tumor grade	[57]
	METTL3	Upregulated	Tumor grade, and overall survival	[58]
	METTL3	Upregulated	Overall survival	[59]
	METTL3	Upregulated	Tumor malignancy, and overall survival	[60]
Prostate cancer	METTL3	Upregulated	Promoter methylation, relapse-free survival, and metastasis	[61]
	METTL3	Upregulated	Overall survival	[62]
	METTL3	Upregulated	Overall survival	[63]
Renal cancer	METTL3	Upregulated	Overall survival, clinical stage, and tumor size	[64]
	METTL3	Upregulated	Overall survival	[65]
Bladder cancer	METTL3	Upregulated	Histological grade, and overall survival	[66]
	METTL3	Upregulated	Histological grade	[67]
Thyroid cancer	METTL3	Downregulation	Recurrence-free survival, and overall survival	[68]
	METTL3	Downregulation	Tumor differentiation, T stage, lymph node metastasis, and the AJCC-defined stage of extrathyroidal extension	[69]

TNM Tumor-Node-Metastasis, AJCC American Joint Committee on Cancer

Recent studies highlight METTL3 as a pivotal regulator of m6A-dependent post-transcriptional gene regulation in cancer. By modifying specific oncogenic or tumor-suppressive transcripts, METTL3 modulates hallmark processes, such as cell proliferation, stemness, metabolic reprogramming, immune evasion, and resistance to chemotherapy and targeted agents (Fig. 2, Table 2). The precise consequences of METTL3 activity vary across cancer types and molecular subtypes.

Fig. 2.

Functional landscape of METTL3-mediated m6A modification in cancer. METTL3 modulates key oncogenic pathways via m6A-dependent post-transcriptional regulation, affecting tumor hallmarks, such as stemness (USP4, NANOG, and HDGF), proliferation (E2F5), migration (P3H4 and USP4), angiogenesis (ADAMTS9), immune evasion (SCAP), and therapy resistance (DDX23). These context-specific targets underscore METTL3’s central role in driving cancer progression across multiple tumor types

Table 2.

Functional roles and mechanisms of METTL3 in tumor progression

Tumor type	METTL3	Role	Functional role	In vivo	Targeted proteins	Refs.
Gastric cancer	METTL3	Tumor promotion	Cell proliferation, angiogenesis, migration, and invasion	Tumor growth, tumor angiogenesis, and liver metastasis	P300, IGF2BP3, HDGF, GLUT4, and ENO2	[37]
	METTL3	Tumor promotion	EMT, cell migration, and invasion	Liver metastasis, and lung metastasis	ZMYM1, CtBP/LSD1/CoREST, and E-cadherin	[38]
	METTL3	Tumor promotion	Cell proliferation, migration, and drug resistance to oxaliplatin		DNA repair	[70]
	METTL3	Tumor promotion	Drug resistance to oxaliplatin		DNA repair	[71]
	METTL3	Tumor promotion	Cell proliferation, and migration		IGF2BP2, STAT5A, and KLF4	[39]
	METTL3	Tumor promotion	Cell proliferation, and angiogenesis		YTHDF2, ADAMTS9, PI3K, and AKT	[40]
Colorectal cancer	METTL3	Tumor promotion	Cell cycle, and migration	Tumor growth, and lung metastasis	JAK1	[41]
	METTL3	Tumor promotion	Cell proliferation, cell cycle, cell apoptosis, and cell stemness	Tumor growth	GLUT1, and mTORC1	[42]
	METTL3	Tumor promotion	Cell stemness, and drug resistance to oxaliplatin	Tumor growth, and lung metastasis	SOX2, and IGF2BP2	[43]
	METTL3	Tumor promotion	Cell migration, and invasion	Liver metastasis, and spleen metastasis	miR-1246, and SPRED2	[44]
Liver cancer	METTL3	Tumor promotion	Antitumor immune response, and aberrant cholesterol biosynthesis	Tumor growth	SCAP	[72]
	METTL3	Tumor promotion	Cell proliferation, and migration	Tumor growth, and lung metastasis	YTHDF2, and SOCS2	[45]
	METTL3	Tumor promotion	Drug resistance to Lenvatinib		EGFR	[46]
	METTL3	Tumor promotion	Stemness	Stemness	SOCS3, JAK2, and STAT3	[47]
Pancreatic cancer	METTL3	Tumor promotion	Stemness	Tumor growth	YTHDF2, ID2, PI3K, AKT, NANOG, and SOX2	[48]
	METTL3	Tumor promotion	Cell proliferation, cell migration, and invasion		E2F5	[73]
	METTL3	Tumor promotion	Cell proliferation, cell migration, and invasion			[50]
	METTL3	Tumor promotion	Cell proliferation, cell migration, invasion, and drug resistance to gemcitabine	Tumor growth	DDX23, PI3K, and Akt	[51]
Lung cancer	METTL3	Tumor promotion	Cell apoptosis, and mitophagy	Tumor growth	DCP2, DCP2, and Pink1–Parkin pathway	[52]
	METTL3	Tumor promotion	Cell proliferation, apoptosis, and cell cycle	Tumor growth	YTHDF1, and SLC7A11	[53]
	METTL3	Tumor inhibition	Cell migration, and invasion		SH3BP5, and YTHDF1	[54]
	METTL3	Tumor promotion	Cell proliferation, migration, and invasion		SFRP2, Wnt, and β-catenin	[55]
	METTL3	Tumor promotion	Cell viability, apoptosis, and migration	Tumor growth	Bcl-2	[56]
Glioma	METTL3	Tumor promotion	Cell proliferation, migration, autophagy, and mitochondrial fission	Tumor growth	LINC00475, and MIF	[58]
	METTL3	Tumor promotion	GSC proliferation, tumorsphere formation, stemness, and TMZ sensitivity	Tumor growth, and response to TMZ	DNA repair gene transcripts	[74]
	METTL3	Tumor promotion	GSC proliferation, neurosphere formation, stemness, apoptosis, TMZ sensitivity, and radiosensitivity	Tumor growth, and survival	SOX2, and HuR	[59]
	METTL3	Tumor promotion	Cell proliferation, migration, colony formation, and cell cycle	Tumor growth, and survival	MALAT1, HuR, and NF-κB	[60]
Prostate cancer	METTL3	Tumor promotion	Cell proliferation, migration, invasion, stemness, and glycolysis	Tumor growth	IGF2BP2, HOXC6, and PGK1	[75]
	METTL3	Tumor promotion	Cell migration, invasion, and lamellipodia formation	Tumor growth, and lung metastasis	YTHDF2, USP4, ELAVL1, and ARHGDIA	[61]
	METTL3	Tumor promotion	Cell proliferation, migration, invasion, and apoptosis,	Tumor growth	miR-148a-3p, and TXNIP	[62]
	METTL3	Tumor promotion	Cell proliferation, migration, invasion, and drug sensitivity	Tumor growth, and drug sensitivity	HRAS, MEK2, and ERK	[76]
	METTL3	Tumor promotion	Cell proliferation, migration, invasion, and stemness	Tumor growth	IGFBP3, and Akt	[63]
Renal cancer	METTL3	Tumor promotion	Cell proliferation, cell migration, and invasion	Tumor growth	HIF-1α, and PLOD2	[64]
	METTL3	Tumor promotion	Cell proliferation, migration, and invasion	Tumor growth	HHLA2	[65]
	METTL3	Tumor promotion	Cell viability, cell proliferation, and apoptosis	Tumor growth	IGF2BP1, and ZHX2	[67]
Bladder cancer	METTL3	Tumor promotion	Cell proliferation, migration, and invasion	Tumor growth	miR-221/222, DGCR8, and PTEN	[66]
	METTL3	Tumor promotion	Cell proliferation, migration, and apoptosis	Tumor growth	MYC, AFF4, RELA, IKBKB, MYC, and NF-κB	[67]
	METTL3	Tumor promotion	Cell viability, migration, invasion, and EMT	Tumor growth	P3H4	[65]
Thyroid cancer	METTL3	Tumor inhibition	Cell proliferation, migration, and invasion	Lung metastasis	c-Rel, RelA, NF-κB, and IL-8	[68]
	METTL3	Tumor inhibition	Cell proliferation, migration, drug resistance to hemotherapeutic drugs, and iodine-131	Tumor growth, and lung metastasis	PAX8, and miR-493-5p	[69]

EMT epithelial–mesenchymal transition

Gastric cancer (GC)

METTL3 is frequently overexpressed in GC and correlates with advanced TNM stage, lymph node metastasis, and reduced progression-free survival (PFS) and overall survival (OS), and post-progression survival (PPS) [37–40, 70, 71]. Functionally, METTL3 promotes proliferation, angiogenesis, and invasion while enhancing resistance to oxaliplatin both in vitro and in vivo [37–40, 70, 71]. Mechanistically, METTL3 is transcriptionally upregulated via p300-mediated H3K27ac (Fig. 3) [37]. It enhances m6A modification of HDGF mRNA, stabilizing it via IGF2BP3, which in turn upregulates GLUT4 and ENO2, promoting glycolytic reprogramming. In addition, METTL3 modifies ZMYM1, which recruits the CtBP/LSD1/CoREST complex to repress E-cadherin, thus facilitating EMT and metastasis [38]. In CD133⁺ GC stem cells, METTL3 upregulates PARP1 to enhance DNA repair and oxaliplatin resistance [70, 71]. METTL3 also cooperates with IGF2BP2 to stabilize STAT5A, which transcriptionally represses KLF4, augmenting invasiveness [39]. Furthermore, METTL3 enhances angiogenesis via ADAMTS9/PI3K/AKT signaling [40]. These findings support METTL3 not only as a prognostic marker, but also as a predictive biomarker for chemotherapy response in GC, with potential to guide future precision therapy based on expression profiling.

Fig. 3.

Mechanistic landscape of METTL3-mediated m6A regulation in gastric cancer

Upregulated in gastric cancer, METTL3 drives tumor progression via m6A-dependent stabilization of key transcripts. Through IGF2BP3, it stabilizes HDGF to enhance glycolysis (GLUT4, ENO2), and promotes EMT via ZMYM1, which recruits CtBP/LSD1/CoREST to repress E-cadherin. METTL3 also stabilizes ADAMTS9, activating the PI3K/AKT pathway to promote angiogenesis. In CD133⁺ cancer stem cells, it induces oxaliplatin resistance by upregulating PARP1, enhancing DNA repair. In addition, it cooperates with IGF2BP2 to stabilize STAT5A, which represses KLF4, thereby enhancing invasiveness and metastasis.

Colorectal cancer (CRC)

METTL3 is markedly overexpressed in CRC and is significantly associated with lymph node metastasis, distant spread, and poor clinical prognosis [41–44]. Elevated METTL3 levels correlate with reduced OS and disease-free survival (DFS), serving as an independent prognostic biomarker [42–44]. Functionally, METTL3 enhances CRC cell proliferation, migration, and stemness while reducing apoptosis and impairing sensitivity to oxaliplatin-based chemotherapy [41–44]. In vivo, METTL3 knockdown significantly suppresses tumor growth and metastasis to the liver, spleen, and lungs [41, 42]. Mechanistically, METTL3-mediated m6A modification promotes translation of JAK1 via YTHDF1, activating the JAK/STAT pathway and driving tumor progression [41]. It also upregulates GLUT1 through m6A methylation, enhancing glucose metabolism and activating the mTORC1 pathway. Inhibition of mTORC1 synergizes with METTL3 knockdown, further suppressing tumor growth [42]. In addition, METTL3 increases SOX2 expression through IGF2BP2 recognition of m6A-modified transcripts, maintaining CRC stemness [43]. METTL3 also induces miR-1246, which downregulates the tumor suppressor SPRED2, leading to MAPK pathway activation and metastasis [44]. From a therapeutic perspective, METTL3 has potential predictive biomarker value. Its overexpression contributes to immune evasion and reduced efficacy of immune checkpoint inhibitors (ICIs), particularly in microsatellite instability-high (MSI-H) subgroups. Thus, METTL3 profiling may help guide patient stratification for ICI therapy in CRC.

Hepatocellular carcinoma (HCC)

METTL3 is consistently overexpressed in hepatocellular carcinoma (HCC), with its expression correlating with advanced tumor stage, histologic grade, vascular invasion, and poor OS and DFS [45–47, 72]. Clinically, METTL3 has emerged as a prognostic marker and a potential target for overcoming therapeutic resistance, particularly to Lenvatinib and immune checkpoint inhibitors. Functionally, METTL3 promotes HCC proliferation, migration, and drug resistance. Its inhibition induces G1-phase arrest, reduces tumor growth in vivo, and sensitizes HCC cells to Lenvatinib [72]. Combined treatment with STM2457 (a METTL3 inhibitor) and Lenvatinib significantly enhances antitumor effects, both in vitro and in xenograft models [46]. At the mechanistic level, METTL3 facilitates HCC progression through multiple m6A-dependent pathways. It promotes cholesterol biosynthesis by stabilizing SCAP mRNA, which suppresses CD8⁺ T cell activity, especially in NAFLD-associated HCC, thereby contributing to immune escape and resistance to anti-PD-1 therapy [72]. METTL3 silences tumor suppressors, such as SOCS2 by m6A tagging, followed by YTHDF2-mediated degradation, relieving negative regulation on the JAK/STAT pathway [45]. It also targets SOCS3, facilitating activation of the SOCS3/JAK2/STAT3 axis, further promoting tumor progression and stem cell expansion [47]. These findings position METTL3 as both a driver of tumor immune evasion and a modulator of therapeutic resistance, making it a candidate for combinatorial strategies involving targeted therapies (e.g., Lenvatinib) and immunotherapy. Future studies integrating METTL3 expression profiling with immunogenomic data may improve treatment stratification in HCC patients.

Pancreatic cancer (PC)

METTL3 is significantly overexpressed in pancreatic cancer and correlates with advanced TNM stage, poor differentiation, and resistance to gemcitabine, a frontline chemotherapeutic agent [48–51, 73]. High METTL3 expression predicts worse overall survival, positioning it as a prognostic biomarker and a potential modulator of therapeutic response [48]. Functionally, METTL3 promotes tumor growth, invasion, stemness, and chemoresistance in PC. METTL3 knockdown enhances gemcitabine sensitivity, suppresses tumor growth in xenograft models, and reduces Ki-67 expression and stem-like traits [48, 51]. Mechanistically, METTL3 regulates PC progression through multiple m6A-dependent axes. METTL3 stabilizes ID2 mRNA via YTHDF2, promoting NANOG and SOX2 expression through the PI3K/AKT pathway, which drives cancer stemness and proliferation [48]. It enhances m6A modification of DDX23 mRNA, increasing its stability. DDX23 activates the PI3K/AKT pathway, and its silencing reverses METTL3-induced malignancy and gemcitabine resistance [51]. METTL3 also induces E2F5 methylation, enhancing its expression. Silencing METTL3 leads to E2F5 destabilization, while E2F5 overexpression partially rescues the anti-proliferative effects of METTL3 inhibition [73]. These pathways collectively contribute to chemoresistance and aggressive phenotypes in PC. Given the observed synergy between METTL3 inhibition and gemcitabine, METTL3 may serve as both a predictive biomarker and a combinatorial target for overcoming drug resistance. Future therapeutic strategies may involve pairing METTL3 inhibitors with DNA damage inducers or autophagy inhibitors to enhance clinical efficacy.

Lung cancer

METTL3 is significantly overexpressed in multiple lung cancer subtypes, including NSCLC, lung adenocarcinoma (LUAD), and small cell lung cancer (SCLC) [52, 53, 55, 56]. Elevated METTL3 expression correlates with poor differentiation, advanced clinical stage, lymph node metastasis, and reduced overall survival (OS), establishing its role as a prognostic marker across lung cancers. In SCLC, METTL3 expression is particularly elevated in chemoresistant cell lines [52]. Mechanistically, METTL3 promotes resistance by catalyzing m6A modification of DCP2, leading to its degradation. Loss of DCP2 activates the PINK1–Parkin mitophagy pathway, which protects mitochondrial integrity and promotes chemoresistance. Importantly, treatment with the METTL3 inhibitor STM2457 reverses resistance to chemotherapy in both in vitro and in vivo models, suggesting a potential synergistic therapeutic strategy in refractory SCLC [52]. In LUAD, METTL3 expression and global m6A levels are markedly increased [53]. METTL3 knockdown induces G0/G1 cell cycle arrest, inhibits tumor growth, and promotes apoptosis. Mechanistically, METTL3 stabilizes SLC7A11 mRNA via YTHDF1 binding, leading to reduced ferroptosis through diminished ROS accumulation and lipid peroxidation [53]. In NSCLC, METTL3 exhibits context-dependent functions. In many NSCLC models, it acts as an oncogene, promoting proliferation, invasion, and drug resistance through m6A modification of targets, such as SFRP2 (activating the Wnt/β-catenin pathway) and Bcl-2 (enhancing cell survival) [55, 56]. However, in EGFR–wild-type A549 and H522 cells, METTL3 may exert tumor-suppressive effects by stabilizing SH3BP5 mRNA through site-specific m6A methylation. YTHDF1 binding maintains SH3BP5 expression, thereby inhibiting migration and invasion [54]. These conflicting findings underscore the subtype-dependent role of METTL3 in NSCLC. For example, EGFR-mutant NSCLC may benefit from METTL3-targeted combination therapies, whereas in wild-type subtypes, METTL3 inhibition might impair tumor-suppressive pathways. Therefore, molecular stratification is essential before applying METTL3-based interventions.

Glioma

METTL3 is significantly overexpressed in high-grade gliomas, particularly in glioblastoma (GBM) and IDH–wild-type subtypes, where its upregulation correlates with tumor aggressiveness, therapy resistance, and poor patient survival [57–60, 74]. Elevated METTL3 expression serves as a prognostic biomarker and is functionally linked to tumor stemness, radioresistance, and treatment failure. Functionally, METTL3 promotes glioma cell proliferation, migration, invasion, and stemness while supporting resistance to temozolomide (TMZ) and radiotherapy. Knockdown of METTL3 impairs glioma stem cell maintenance, reduces DNA repair capacity, and enhances sensitivity to both TMZ and ionizing radiation [57–59, 74]. Mechanistically, METTL3 drives gliomagenesis via multiple m6A-dependent pathways. It stabilizes SOX2 mRNA through 3′UTR m6A modification, enhancing HuR-mediated RNA protection. This maintains glioma stem-like properties and promotes radioresistance [59]. METTL3 facilitates alternative splicing of LINC00475 by recruiting HNRNPH1 to m6A-marked regions, generating the oncogenic LINC00475-S variant. This splicing suppresses MIF, a negative regulator of mitochondrial fission, thereby increasing DRP1/p-DRP1 and decreasing OPA1/MFN2, promoting tumor progression [58]. It stabilizes MALAT1 lncRNA via m6A, which activates NF-κB signaling, contributing to glioma cell proliferation, migration, and inflammatory microenvironment remodeling [60]. In TMZ-resistant glioma cells, METTL3 enhances DNA repair and suppresses apoptosis, contributing to therapeutic resistance. METTL3 also maintains glioma stem cell populations by stabilizing stemness regulators, such as SOX2 and NANOG, reinforcing its role as a key epigenetic modulator of therapy failure [59]. Notably, METTL3 knockdown increases γ-H2AX accumulation post-irradiation, indicating impaired DNA damage repair, thus sensitizing glioma cells to radiotherapy. These findings highlight METTL3 as a predictive biomarker for radio- and chemoresistance, and suggest its inhibition could improve response to standard GBM therapies.

Prostate cancer (PCa)

METTL3 is significantly overexpressed in high-grade gliomas, particularly in glioblastoma (GBM) and IDH–wild-type subtypes, where its upregulation correlates with tumor aggressiveness, therapy resistance, and poor patient survival [61–63, 75, 76]. Elevated METTL3 expression serves as a prognostic biomarker and is functionally linked to tumor stemness, radioresistance, and treatment failure. Functionally, METTL3 drives cell proliferation, invasion, stemness, and glycolytic reprogramming through m6A-dependent mechanisms. In vivo and in vitro knockdown of METTL3 reduces tumor burden, inhibits metastasis, and downregulates oncogenic markers, such as Ki-67, HOXC6, and PGK1 [61–63, 75, 76]. METTL3 stabilizes HOXC6 mRNA via IGF2BP2, promoting transcriptional activation of PGK1, a key glycolytic enzyme. This pathway contributes to enhanced aerobic glycolysis and tumor progression [75]. In addition, METTL3 promotes the maturation of miR-148a-3p, which suppresses TXNIP, a tumor suppressor involved in oxidative stress regulation. This enhances cell survival and growth [62]. In CRPC, METTL3 increases m6A modification of HRAS and supports MEK2 translation, thereby sustaining ERK pathway activation and promoting enzalutamide resistance [76]. METTL3-mediated m6A tagging triggers YTHDF2-dependent decay of USP4 mRNA, while destabilization of ELAVL1 and stabilization of ARHGDIA mRNAs further contribute to metastasis [61]. Preclinical studies show that the METTL3 inhibitor STM2457 suppresses PCa cell proliferation, migration, and colony formation. In both CDX and PDX models, STM2457 significantly reduces tumor volume and restores IGFBP3 expression by decreasing its m6A methylation, thereby attenuating the AKT signaling pathway [63, 76]. Moreover, combined treatment with STM2457 and PARP inhibitors (e.g., olaparib) or enzalutamide exerts synergistic anti-tumor effects, particularly in drug-resistant CRPC [63]. These findings support the potential of METTL3 as a combination target in precision therapy for advanced PCa.

Renal cell carcinoma (RCC)

METTL3 is significantly upregulated in ccRCC, with elevated expression correlating with larger tumor size, advanced clinical stage, and poor prognosis [65–67]. Functionally, METTL3 enhances tumor growth, invasion, and resistance to apoptosis through multiple m6A-dependent regulatory pathways [64, 65, 67]. Knockdown of METTL3 reduces cell proliferation, induces apoptosis, and significantly suppresses tumor growth in vitro and in xenograft models [64, 65, 67]. The pro-tumorigenic effects of METTL3 in RCC are mediated through several m6A-modified oncogenic targets. Under hypoxic conditions, METTL3 is transcriptionally activated by HIF-1α and promotes m6A modification of PLOD2 mRNA, increasing its stability and translation. PLOD2 enhances extracellular matrix remodeling and metastatic potential [64]. METTL3 also stabilizes HHLA2 mRNA, an immune checkpoint molecule of the B7 family, which contributes to immune evasion and tumor progression [65]. This highlights METTL3’s potential role in shaping the tumor immune microenvironment in RCC. In addition, through m6A modification and IGF2BP1 recognition, METTL3 enhances the expression of ZHX2, a transcription factor that drives angiogenesis, metastasis, and stem-like phenotypes in RCC cells [67]. Pharmacological inhibition of METTL3 with STM2457 recapitulates the effects of genetic silencing, including suppression of cell proliferation, downregulation of oncogenic markers, and reduced tumor volume in vivo [64]. These findings support the feasibility of METTL3-targeted therapy in RCC. Given the involvement of METTL3 in stabilizing HHLA2, a molecule implicated in immune checkpoint regulation, METTL3 inhibition may also enhance the efficacy of ICIs. This represents a promising area for future combinatorial strategies.

Bladder cancer (BCa)

METTL3 is significantly overexpressed in BCa, and its upregulation is closely associated with high tumor grade, poor prognosis, and aggressive clinical behavior [65–67]. Functionally, METTL3 enhances tumor growth, invasion, and resistance to apoptosis through multiple m6A-dependent regulatory pathways [65–67]. Mechanistically, METTL3 promotes the maturation of oncogenic miR-221/222 in an m6A-dependent manner, facilitated by DGCR8-mediated processing, which subsequently downregulates the tumor suppressor PTEN [66]. Transcriptome and m6A profiling further indicate that METTL3 modulates key oncogenic pathways, including MYC and NF-κB, by m6A modification of targets, such as MYC, AFF4, RELA, and IKBKB [67]. In addition, METTL3 knockdown increases the expression of epithelial–mesenchymal transition (EMT) markers, suggesting its role in EMT induction and tumor progression [65]. These observations support a central oncogenic function for METTL3 in BCa pathogenesis. Preclinical models suggest that METTL3 may serve as a predictive biomarker for aggressive BCa subtypes.

Papillary thyroid carcinoma (PTC)

In PTC, METTL3 is significantly downregulated, and reduced expression is associated with poor tumor differentiation, advanced TNM stage, lymph node metastasis, and shortened recurrence-free and overall survival [68, 69, 77]. These findings suggest a tumor-suppressive role for METTL3 in PTC, distinct from its oncogenic function in many other malignancies. Experimental studies demonstrate that METTL3 inhibits PTC cell proliferation, migration, and invasion, and enhances sensitivity to chemotherapy (e.g., cisplatin and doxorubicin) and radioiodine therapy in an m6A-dependent manner [68, 69]. Mechanistically, METTL3 increases m6A modification of PAX8 mRNA, a thyroid-specific transcription factor crucial for cell differentiation. The m6A reader YTHDC1 stabilizes PAX8 in the nucleus, maintaining differentiated phenotypes and limiting tumor progression [69]. In addition, METTL3 destabilizes mRNAs of c-Rel and RelA, leading to downregulation of IL-8, a key chemoattractant for tumor-associated neutrophils (TANs). This mechanism impairs inflammatory microenvironment formation, thereby reducing immune cell-driven tumor progression [68]. On the post-transcriptional level, miR-493-5p targets METTL3, forming a negative feedback loop that promotes PTC aggressiveness by silencing METTL3 expression. Upregulation of this miRNA correlates with poorer patient prognosis [69]. Given its inverse correlation with tumor aggressiveness and its role in maintaining differentiation and radioiodine sensitivity, METTL3 may serve as a prognostic biomarker and a predictive marker for therapy response in PTC.

Clinical implications of METTL3 in cancers

Current preclinical studies

The identification of METTL3 as a key oncogenic driver in multiple malignancies has stimulated the development of selective small-molecule inhibitors, most notably STM2457, the first-in-class METTL3 inhibitor. In acute myeloid leukemia (AML), STM2457 inhibits METTL3’s methyltransferase activity, reducing m6A levels and translation of oncogenic transcripts, thereby promoting cell differentiation and apoptosis [69]. Preclinical evidence also supports STM2457’s efficacy in CRPC by disrupting the IGFBP3/AKT pathway and sensitizing tumors to PARP inhibitors (e.g., olaparib), enhancing DNA damage responses in both cell lines and PDX models [63]. In CRC, STM2457 suppresses proliferation by downregulating the m6A-modified gene ASNS [78], while in NSCLC, it enhances paclitaxel and carboplatin sensitivity by destabilizing ABCC2 mRNA, a drug efflux transporter [79]. Additional research demonstrates that STM2457 exerts antitumor effects in oral squamous cell carcinoma (OSCC) through EMT inhibition and EGFR downregulation, especially in combination with anlotinib [80], and impedes metastasis in pancreatic cancer by repressing m6A modification of BANCR lncRNA [81]. Despite promising preclinical outcomes, STM2457 has yet to enter clinical evaluation, underscoring the urgent need for early phase trials to establish its safety, efficacy, and potential for combination regimens.

Challenges in targeting METTL3

Targeting METTL3 presents several biological and pharmacological challenges. Although STM2457 shows high biochemical selectivity, off-target effects on other methyltransferases (e.g., METTL1 and METTL16) and demethylases (e.g., FTO) have been reported [82]. METTL3 also plays critical roles in normal physiology, including hematopoiesis and immune cell homeostasis; systemic inhibition could, therefore, lead to hematologic toxicity or immune dysregulation [83]. For instance, suppression of METTL3 in hematopoietic stem cells disrupts lineage commitment and cell renewal, posing a major safety concern in therapies targeting solid tumors.

In terms of pharmacokinetics, STM2457 suffers from limited tumor penetration and variable bioavailability, especially in tumors with dense stromal barriers. New-generation inhibitors such as EP652 demonstrate improved oral bioavailability and metabolic stability [84]. In addition, peptide-based inhibitors disrupting the METTL3–METTL14 interaction offer a promising strategy with potentially higher specificity and reduced off-target profiles [85]. Importantly, METTL3 exhibits context-dependent behavior: while acting as an oncogene in AML, LUAD, and CRC, it may exert tumor-suppressive effects in certain subtypes of NSCLC and PTC [37, 42, 54, 68]. Therefore, blanket inhibition of METTL3 may produce paradoxical effects, depending on tissue type, genetic context, and treatment combination. Consequently, the development of predictive biomarkers and companion diagnostics is essential for identifying patient subgroups most likely to benefit from METTL3-targeted therapies.

METTL3 as a prognostic and predictive biomarker and a synergistic therapeutic target

Growing evidence highlights the dual value of METTL3 as both a prognostic and predictive biomarker across cancer types. METTL3 serves both prognostic and predictive roles depending on tumor context. Prognostically, METTL3 overexpression correlates with adverse clinical outcomes in lung, gastric, bladder, and colorectal cancers, largely due to its role in promoting oncogenic processes [37, 41, 48, 52, 57, 66, 72, 75]. Elevated METTL3 expression consistently correlates with advanced TNM stages, increased lymphatic and distant metastasis, and poorer clinical outcomes. For example, in gastric cancer, METTL3 overexpression independently predicts shorter PFS and OS, and is recognized as an independent prognostic marker [37]. Likewise, in colorectal, hepatic, pancreatic, and prostate cancers, elevated METTL3 levels are associated with enhanced invasiveness, reduced chemotherapy sensitivity, and adverse survival outcomes [43, 46, 48, 61]. Overexpression of METTL3 in BCa and ccRCC also serves as a predictor of poor prognosis and aggressive disease progression [65, 66]. Conversely, METTL3 downregulation has been reported in specific cancers, such as PTC, where it correlates with lower tumor differentiation and increased recurrence [68, 69, 77]. Reduced METTL3 expression is associated with advanced tumor stages (T stage), lymph node metastasis, and decreased recurrence-free and overall survival rates [68, 69].

Predictively, high METTL3 expression correlates with resistance to EGFR–tyrosine kinase inhibitors (TKIs) in LUAD and ICIs in CRC [86, 87]. Similarly, in gastric cancer, β-elemene reverses cisplatin resistance by altering exosomal METTL3-mediated ARF6 methylation [88]. In addition, the combination of METTL3 inhibition with other cancer therapies may offer synergistic effects. In EGFR-mutant lung cancer, METTL3 promotes resistance to TKIs by stabilizing resistance-associated transcripts (e.g., NLRP3) and enhancing classical pyroptosis signaling pathways [89]. In AML, pharmacologic inhibition of METTL3 enhances the efficacy of chemotherapy, reducing leukemic burden [90]. Together, these findings position METTL3 not only as a therapeutic target but also as a strategic node for synergistic combination therapies, particularly with EGFR–TKIs, PARP inhibitors, and immunotherapy. Rational design of such regimens will require a better understanding of tumor subtype, immune contexture, and m6A signaling dependencies. In the long term, integration of METTL3-targeted agents into personalized oncology pipelines will depend on predictive profiling of m6A regulators, methylation landscapes, and RNA decay dynamics in individual tumors.

Conclusions and perspectives

Over the past decade, m6A RNA methylation, largely catalyzed by METTL3, has emerged as a key layer of post-transcriptional gene regulation in cancer. Substantial evidence positions METTL3 as a context-dependent regulator, exerting either oncogenic or tumor-suppressive effects depending on tumor type, cellular origin, and microenvironmental context. In most malignancies, it promotes tumor progression and therapy resistance via m6A-mediated stabilization of oncogenic transcripts. The development of selective inhibitors such as STM2457 has demonstrated promising preclinical efficacy and combinatorial potential with chemotherapy, EGFR–TKIs, and immunotherapies. However, challenges including off-target effects, delivery barriers, and physiological toxicity must be addressed. Future success will depend on biomarker-driven patient stratification and deeper mechanistic insights into METTL3-regulated epitranscriptomic networks.

Abbreviations

m6A

N6-methyladenosine

mRNAs

Messenger RNAs

SAM

S-adenosylmethionine

PFS

Progression-free survival

OS

Overall survival

DFS

Disease-free survival

PPS

Post-progression survival

PTC

Papillary thyroid carcinoma

GC

Gastric cancer

CRC

Colorectal cancer

SCLC

Small cell lung cancer

LUAD

Lung Adenocarcinoma

NSCLC

Non-small cell lung cancer

OSCC

Oral squamous cell carcinoma

HCC

Hepatocellular carcinoma

NAFLD–HCC

Non-alcoholic fatty liver disease-associated HCC

PC

Pancreatic cancer

GBM

Glioblastoma

TMZ

Temozolomide

PCa

Prostate cancer

CRPC

Castration-resistant prostate cancer

RCC

Renal cell carcinoma

ccRCC

Clear cell renal cell carcinoma

BCa

Bladder cancer

AML

Acute myeloid leukemia

ICIs

Immune checkpoint inhibitors

Author contributions

Huihui Gao and Fang Yuan designed and guided the review. Fang Yuan and Wenjuan Zhang participated in original draft preparation. Yuxuan Xia and Xiangqin Zhou designed the figures and completed the table. All the authors contributed to the manuscript and reviewed and approved the published version of the manuscript.

Funding

This work was supported by the Zhejiang Provincial Medical and Health Science and Technology Program: Research and Application of a Tumor Staging NLP Model for Improving Cancer Care Quality (2023KY555).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.