METTL1, a methyltransferase involved in the m⁷G modification of RNA, is differentially expressed across various cancer types (Table 1). Previously, METTL1 was found to be overexpressed in diverse malignancies, including colorectal cancer (CRC) (36, 37), HCC (15, 20, 38), and esophageal cancer (ESCA) (26). Its high expression has been correlated with poor prognosis. In HCC, METTL1 expression is closely associated with tumor malignancy and poor prognosis. Clinical data analysis revealed that high METTL1 expression correlates significantly with larger tumor size, elevated serum AFP levels, tumor vascular invasion, and reduced survival rates. METTL1 was confirmed as an independent prognostic factor for unfavorable outcomes in two independent cohorts (15). Furthermore, in the context of HCC, WDR4 plays a crucial role in functionally interacting with METTL1, thereby enhancing METTL1 expression stability. This interaction is pivotal for the regulation of m⁷G tRNA methylation on target transcripts, which in turn promotes tumor advancement (39). In lung cancer, METTL1/WDR4-mediated m⁷G tRNA modification functions as an oncogenic driver through changing translational efficiency of m⁷G tRNA codon-enriched mRNAs (8). METTL1 is aberrantly elevated in acute myeloid leukemia (AML) and drives leukemogenesis by enhancing tRNA m⁷G modification, stabilizing tRNA to promote translation efficiency and cell proliferation, while its depletion disrupts these processes and induces apoptosis, highlighting its potential as a therapeutic target in AML (40). Single nucleotide polymorphisms (SNPs) within the METTL1 gene could serve as potential biomarkers for the identification of at-risk populations for neuroblastoma. This is supported by evidence suggesting a correlation between variations in genes associated with m⁷G modifications, including METTL1 SNPs, and the risk of developing neuroblastoma (41, 42). While METTL1 predominantly acts as an oncogenic driver in most malignancies, emerging evidence reveals its context-dependent tumor-suppressive functions in specific cancer types. Recent research has indicated that higher METTL1 expression is associated with improved patient survival compared to lower expression in gastric cancer patients (43). Hypoxia-induced HIF-1α downregulates the transcription of METTL1 in CRC cells. Such downregulation leads to a notable reduction in m⁷G modifications, thereby expediting the progression of CRC (37). The highly heterogenous expression profile of METTL1 in various cancers suggests that it may serve as a biomarker of cancer progression and a target for therapeutic intervention. We have summarized the latest findings on the function and related mechanisms of METTL1 in diseases (Figure 2).

In recent years, there has been renewed interest in studying the role of METTL1 in cancer growth and progression (15, 35, 44). Notably, METTL1 facilitates cell proliferation by modulating the stability and translation of mRNAs via the m⁷G modification (13, 14). For instance, METTL1 significantly enhances the stability of circKDM1A by recognizing its GG motif and catalyzing m⁷G modification. This modification reduces the minimum free energy (MFE) of the RNA secondary structure and prolongs its half-life. The stabilized circKDM1A acts as a miRNA sponge in the cytoplasm by specifically adsorbing miR-147b-3p through binding to the Argonaute RISC Catalytic Component 2 (AGO2) protein. This interaction alleviates the inhibitory effect of miR-147b-3p on its target gene, Pyruvate Dehydrogenase Kinase 1 (PDK1). The upregulated PDK1 further phosphorylates and activates AKT Serine/Threonine Kinase (AKT)signaling pathway, driving CRC progression (36). Emerging studies show that METTL1 promotes CRC cell proliferation and G₁/S phase transition through via a CHEK2-dependent mechanism (45). Similar observations have been made in ESCA, where METTL1 enhanced the proliferation and migration by interacting with TSPEAR-AS2, a lncRNA that activates the interferon signaling pathway (46). Another investigation showed that METTL1 facilitated the growth of head and neck squamous cell carcinoma (HNSCC) cells by stabilizing Cyclin Dependent Kinase 4 (CDK4) mRNA, a critical regulator of the cell cycle (35). Recent studies in oral squamous cell carcinoma (OSCC) demonstrate that METTL1 overexpression correlates with poor prognosis. It promotes tumor proliferation by catalyzing m⁷G modification on NEK1 mRNA, which enhances its stability and ultimately induces G₁/S phase transition (47). METTL1 enhances LSM14A mRNA Processing Body Assembly Factor (LSM14A) mRNA stability and translation by m⁷G methylating it in a complex with WDR4, increasing LSM14A protein expression. In the G₁/S phase, LSM14A interacts with RNA helicase DDX5 in the cytoplasm, inhibiting its degradation and stabilizing its levels. This accumulation of DDX5 promotes G₁/S transition by downregulating P21 and upregulating CDK4, while activating migration-related proteins like Matrix Metallopeptidase2/9 (MMP2/9), driving glioblastoma cell proliferation (48). Similarly, METTL1 promotes the progression of AML by regulating tRNA m⁷G modification through two synergistic mechanisms: (1) tRNA stability regulation: METTL1 knockout significantly reduces m⁷G modification at position 46 of tRNAs14. This reduction makes tRNAs more susceptible to degradation by RNase A/T1. Consequently, tRNA abundance decreases, and abnormal accumulation of tRNA-derived small RNA fragments occurs; (2) protein translation control: Loss of m⁷G modification suppresses global translation efficiency by reducing ribosome loading. This leads to decreased synthesis of pro-survival proteins, which causes G₁-phase cell cycle arrest and increased apoptosis in AML cells (40). Although METTL1 has been widely characterized as an oncogenic driver across multiple malignancies, recent studies challenge this unidimensional perspective. Paradoxically, METTL1 demonstrates context-dependent tumor-suppressive activity, particularly in cancers with specific molecular vulnerabilities—such as BRCA1-deficient breast cancer (BRCA) or IDH-mutant gliomas—where it restricts tumor progression through mechanisms involving tRNA modification-mediated cell cycle arrest (G₂/M phase prolongation) and enhanced genome stability maintenance (49). The data reviewed here reveal that METTL1 exerts context-dependent roles in cancer biology, either promoting or suppressing tumorigenesis through m⁷G-mediated regulation of RNA metabolism, which dynamically impacts cancer cell proliferation, survival, and progression.

In recent years, METTL1 has revealed its unique and complex role in regulating apoptosis and autophagy. It exerts a core function by influencing m⁷G modification of specific RNAs, thereby regulating cellular survival and death decisions. Regarding apoptosis, METTL1 promotes the expression of caspase-3 and caspase-9 to activate apoptotic signaling pathways (40). It also induces mitochondrial membrane potential depolarization by regulating membrane potential stability (50), and affects the expression of antioxidant genes to modulate reactive oxygen species (ROS)-mediated oxidative stress and apoptosis activation (51). This functional complexity parallels other regulatory proteins like Trim45—an E3 ubiquitin ligase that precisely controls protein degradation through the ubiquitin-proteasome system—which similarly impacts cell fate decisions in cancers including cervical cancer and glioblastoma (52). In terms of autophagy, METTL1 impacts tRNA translation efficiency via m⁷G modification, thereby regulating the activity of the ULK1 complex and the mTOR signaling pathway. For instance, in esophageal squamous cell carcinoma, METTL1 suppresses the translation of oncogenic transcripts and promotes autophagy-associated cell death (26, 53), while in lung adenocarcinoma, it inhibits autophagy through the AKT/mTORC1 pathway (54). The expression level of METTL1 exhibits a threshold effect on cell fate; high expression influences tumor prognosis by promoting apoptosis or inhibiting autophagy (22). By regulating downstream pathways like PI3K-Akt, METTL1 acts as a molecular switch determining cell fate choice. A comprehensive analysis of current research demonstrates that METTL1 influences cell fate through multiple mechanisms, including epigenetic modifications, signaling pathway regulation, and metabolic reprogramming, revealing its complex role in disease contexts.

The involvement of METTL1 in tumor metastasis is increasingly being recognized (20, 29, 55). In various cancer types, METTL1 enhanced the proliferation and invasion of tumor cells by activating the translation of mRNAs containing codons decoded by m⁷G-modified tRNAs (28, 29, 56, 57, 58). METTL1-mediated m⁷G tRNA modification selectively promotes oncogenic mRNA translation via codon-frequency-dependent mechanisms to drive intrahepatic cholangiocarcinoma (ICC) progression. This regulatory process operates through two sequential mechanisms: (1) METTL1 deficiency decreases m⁷G-modified tRNA (e.g., LysCTT) abundance, inducing ribosome stalling at high-frequency codons (e.g., AAG) and preferentially suppressing translation of codon-enriched oncogenic transcripts like Cyclin-A2 (CCNA2) and Epidermal Growth Factor Receptor (EGFR); (2) Resultant translational repression reduces protein expression of cell cycle regulators (CCNA2, CDK6) and EGFR signaling components (EGFR, AKT, mTOR), ultimately inhibiting ICC proliferation and invasion (29). In HNSCC, METTL1/WDR4 catalyzes m⁷G modifications on tRNAs (primarily at the “RRGGYYS” motif within the V-loop) to stabilize specific tRNAs, thereby enhancing the efficient translation of codons dependent on m⁷G-modified tRNAs (e.g., ValACC) by ribosomes. When METTL1 is functionally impaired, reduced m⁷G modification levels lead to ribosome pausing at these codon sites, significantly compromising decoding efficiency. This translational impairment is particularly enriched in mRNAs of PI3K/AKT/mTOR pathway-related genes, as their open reading frames exhibit high dependency on m⁷G tRNA-specific codons. METTL1 deficiency diminishes the synthesis of key proteins in this pathway, ultimately suppressing HNSCC cell proliferation and metastasis (56). In cutaneous squamous cell carcinoma (CSCC), METTL1 stabilizes Activating Transcription Factor 4 (ATF4) mRNA and increases its expression via m⁷G methylation. Importantly, restoring ATF4 levels leads to glycolytic metabolic reprogramming in tumor cells and counteracts the anti-tumor effects caused by METTL1 knockdown (59). In HCC with insufficient radiofrequency ablation (iRFA), METTL1 enhances translation of Snail Family Transcriptional Repressor 1(SNAIL1) and Snail Family Transcriptional Repressor 2(SNAIL2), key epithelial-mesenchymal transition (EMT) regulator, thereby driving heat stress-induced metastatic progression (60). M⁷G drives BRCA metastasis via EMT and immunosuppression. High m⁷G synergizes with Transforming Growth Factor Beta 1/Macrophage Migration Inhibitory Factor (TGF-β/MIF) to promote invasion, while METTL1/WDR4 regulate metastasis genes and correlate with advanced stages. The m⁷G-TME classifier identifies aggressive (m⁷G-high + TME-low) and favorable prognosis subgroups (m⁷G-low + TME-high), highlighting m⁷G-TME interplay as a metastasis regulator (61). The associations among METTL1, m⁷G modification, and the metastatic potential of tumors underscore the importance of this enzyme in the broader context of cancer biology.

Several investigations have indicated that METTL1 plays a role in the TME, influencing tumor immunity (56, 67). In HCC, it stimulates TGF-β2 translation, which subsequently induces the accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and inhibits CD8⁺ T cell infiltration, thereby fostering the creation of an immunosuppressive microenvironment (68). In clear cell renal cell carcinoma (ccRCC), the upregulation of METTL1 is associated with disease advancement and a heightened presence of immunosuppressive regulatory T cells (Tregs). The underlying mechanism suggests that METTL1 overexpression may promote tumor immune evasion by establishing an immunosuppressive microenvironment predominantly characterized by Tregs (62). In HNSCC, m⁷G modification drives an immunosuppressive tumor microenvironment through multi-dimensional mechanisms. A prognostic model based on m⁷G-related genes showed that high-risk scores were significantly associated with reduced CD8⁺ T cell infiltration and increased M2 macrophages. This effect was mediated by upregulation of Programmed Cell Death Ligand 1 (PD-L1). Single-cell sequencing revealed 1.8–2.5-fold upregulation of glycolysis genes in m⁷G-high cells, promoting Treg differentiation and CD8⁺ T cell inhibition through lactate accumulation. This study first elucidated the LINC00707/miR-30b-5p/LARP1 axis as a central regulatory pathway in m⁷G-mediated immune suppression (69). Additionally, in CRC, the modification of PKM2 mRNA by METTL1 through m⁷G enhances the expression of PKM2, leading to the establishment of a positive feedback loop involving histone H3K9 lactylation (H3K9la), METTL1, and PKM2. This loop functions as follows: PKM2 facilitates glycolysis and lactate production, while lactate subsequently activates METTL1 through H3K9la. This regulatory axis promotes immune evasion in CRC by transcriptionally activating CD155, thereby reinforcing the METTL1-m⁷G-dependent signaling pathway of PKM2 (70). To further support the immunosuppressive role of METTL1, a prior study demonstrated that it regulates several chemokines, such as C-X-C Motif Chemokine Ligand 8 (CXCL8), which modulate the recruitment of immunosuppressive cells (71). Moreover, modifies the immune landscape of tumor cells, altering the interactions between the tumor and stromal cells, hindering anti-tumor immunity (56). METTL1 orchestrates tumor immune evasion across multiple cancers by modulating immunosuppressive microenvironments through distinct mechanisms, positioning it as a promising therapeutic target to enhance immunotherapy efficacy.

Prior investigations have uncovered an association between METTL1 and immune checkpoint molecules, further supporting its role in tumor immunology (71, 72). Moreover, the expression level of METTL1 can alter the transcription of immune checkpoints such as PD-1 and Cytotoxic T-Lymphocyte-Associated Protein 4(CTLA-4), which modulates T cell responses (16, 73). A study on gastric cancer showed that overexpression of METTL1 promoted CTLA-4 and PD-1 expression, suggesting that METTL1 may facilitate immune evasion by enhancing the expression of these inhibitory checkpoints (43). Other scholars have demonstrated that METTL1 can modify the immune microenvironment by regulating the infiltration of various immune cell types, including T cells and macrophages, thereby affecting anti-tumor immune responses (72, 74). This cross-communication suggests that inhibiting METTL1 may improve the efficacy of immune checkpoint inhibitors and hence, the outcomes of patients receiving immunotherapy. Overall, the available evidence confirms that METTL1 is associated with immune checkpoints, making it an important regulator of cancer immunology and a therapeutic target.

The TME also contains stromal cells, which include fibroblasts and immune cells (75–77). Recent studies have demonstrated that METTL1 modulates the behavior of stromal cells in the TME (25, 56, 78).

METTL1 regulates gene expression in stromal cells: in CRC, METTL1 modulates the expression of PKM2 through m⁷G mRNA modification, thereby promoting metabolic reprogramming and immune escape in tumor cells (70). Additionally, METTL1 enhances the translation of specific oncogenes via m⁷G tRNA modification, facilitating stromal cell functionality and gene expression within the TME (56). These findings highlight METTL1’s dual role in both tumor cells and stromal compartments.

METTL1 influences stromal cell differentiation and function: METTL1 significantly impacts stromal cell differentiation and specific functional states, such as immunosuppressive activity and cytokine secretion profiles, across multiple cancer types. For example, METTL1 upregulation drives the differentiation of tumor-associated stromal cells, which in turn amplifies their immunosuppressive functions and reduces CD8⁺ T cell infiltration in HCC (68). Consequently, this highlights METTL1’s critical role in facilitating immune evasion by modulating stromal cell behavior. METTL1 orchestrates TME formation and progression by regulating stromal cell gene expression and functional dynamics. These mechanisms position METTL1 as a pivotal therapeutic target for disrupting tumor-stroma crosstalk.

As a pivotal m⁷G methyltransferase, the biological functions of METTL1 primarily manifest in its m⁷G modification of RNA, participating in the m⁷G modification processes of diverse RNA species—including tRNA, mRNA, and ribosomal RNA (rRNA)—and playing a critical role in the progression of multiple malignancies (18, 20, 58, 67).

Catalytic mechanism of METTL1 in tRNA m⁷G modification: AS the core component of the methyltransferase complex, METTL1 collaborates with WDR4 to introduce m⁷G methylation at position 46 of the variable loop (G46) in tRNAs. This modification significantly enhances the structural stability of specific tRNAs and optimizes ribosomal decoding efficiency by modulating their tertiary conformation. Under METTL1 overexpression, m⁷G-modified tRNAs preferentially recognize complementary codons (e.g., GTG-enriched codons in Growth Arrest And DNA Damage Inducible Alpha (GADD45A) mRNA and CGC codons in RB Transcriptional Corepressor 1 (RB1) mRNA), promoting ribosome translocation on target mRNAs in a codon-biased manner. By accelerating the decoding of m⁷G-associated codons, METTL1 selectively enhances the translational efficiency (TE) of GADD45A and RB1—rather than globally regulating all mRNAs. This tRNA modification-mediated translational upregulation ultimately elevates GADD45A and RB1 protein levels, activating cell cycle checkpoints to induce G₂/M phase arrest, thereby suppressing BRCA progression (49). METTL1 maintains tRNA m⁷G modification to inhibit the biogenesis of 5′TOG fragments, thereby regulating specific translational programs and suppressing interferon pathway activation. Targeting METTL1 can enhance immunotherapy efficacy by reprogramming the TME. This approach provides a novel potential therapeutic strategy for prostate cancer treatment (63).

Role of METTL1 in mRNA methylation and cancer pathogenesis: METTL1-mediated mRNA methylation also plays a key role in tumorigenesis (3, 35). For instance, METTL1 stabilizes Ribosomal RNA Processing 9, U3 Small Nucleolar RNA Binding Protein (RRP9) mRNA via m⁷G modification, thereby promoting tumor cell proliferation and metastasis in CRC.

Structural Insights into METTL1-Dependent miRNA Maturation: Mechanistic studies demonstrate that the METTL1/WDR4 complex recognizes G-rich regions in pri-miR-760 and introduces m⁷G modifications via SAM-dependent catalytic reactions. These modifications enhance the cleavage efficiency of the Drosha/DGCR8 complex, accelerating miR-760 maturation. This m⁷G-dependent regulatory axis culminates in mature miR-760-mediated degradation of the tumor suppressor ATF3 mRNA, driving BLCA cell proliferation, migration, and in vivo metastasis (18). The METTL1-mediated m⁷G modification at the G11 site of the let-7e-5p precursor, also known as primary microRNA (pri-miRNA), enhances DROSHA cleavage efficiency by disrupting the precursor’s inhibitory G-quadruplex structure. This methylation suppresses G-quadruplex formation through interference with Hoogsteen base-pairing, as confirmed by 7-deazaguanosine (DAG) substitution restoring processing efficiency. Loss of METTL1 reduces mature let-7e levels by 60%, upregulating the oncogenic target High Mobility Group AT-Hook 2 (HMGA2) and promoting cancer cell migration (79). In short, METTL1 serves as a central regulator of diverse RNA modifications, profoundly influencing tumor initiation and progression. Its multifaceted roles establish METTL1 as a critical target in cancer research, offering promising avenues for therapeutic intervention.

The various signaling pathways through which METTL1 regulates cancer progression are shown in Figure 3. The role of PI3K/Akt and MAPK pathways in mediating the effects of METTL1 have been widely documented (15, 57). In HCC, METTL1 overexpression was reported to be correlated with larger tumor sizes and poor prognosis, primarily by activating the PTEN/AKT signaling pathway. Moreover, overexpression of METTL1 resulted in decreased PTEN expression, leading to elevated AKT activity, promoting cell proliferation and migration (15). In HCC, the m⁷G methylation facilitated by METTL1 is responsible for the regulation of circIPP2A2, which functions as a molecular scaffold. This interaction enhances the association between Hornerin and PI3K, subsequently activating the PI3K/AKT/GSK3β signaling cascade. This pathway plays a crucial role in promoting the aggressiveness of HCC (80). Similarly, METTL1 promoted tumor progression by modulating the expression of oncogenic transcripts via the PI3K/AKT/mTOR signaling pathway in HNSCC. METTL1 knockdown induced reduction in m⁷G levels of tRNAs that translate these oncogenic mRNAs, which inhibited tumor growth (56). Additionally, the MAPK pathway has been recognized as a crucial factor in promoting the invasive growth of ameloblastoma. METTL1 enhances translation efficiency of MAPK signaling genes (e.g., Ras, BRAF, MEK1/2, ERK1/2) in ameloblastoma without altering their mRNA levels. RNC-seq profiling shows METTL1 depletion selectively impairs translation of MAPK-related transcripts, while qRT-PCR confirms unchanged transcription. This tRNA-specific modification—distinct from mRNA methylation mechanisms—downregulates translation of downstream effectors (Cyclin D1, MMP2/9, Vimentin), establishing tRNA m⁷G-driven translational control of MAPK pathway activation (57). Collectively, these findings indicate that METTL1 serves as a critical regulator of the PI3K/Akt and MAPK signaling pathways, contributing to the malignant phenotypes of various cancers.

METTL1 has emerged as a promising therapeutic target due to its oncogenic role in regulating RNA stability and translation via m⁷G modifications. Current drug development efforts focus on three primary strategies.

Small-molecule inhibitors: A pioneering study first identified METTL1 inhibitors through high-throughput docking and a luminescence-based enzymatic assay, where eleven compounds from three distinct chemotypes demonstrated inhibitory activity in the 40–300 μM range, with adenine derivatives exhibiting high ligand efficiency, highlighting their optimization potential. Molecular dynamics simulations revealed these inhibitors competitively block the binding of the co-substrate SAM to METTL1’s catalytic pocket, with structural validation achieved using a soakable crystal form resolving complexes at 1.85 Å resolution (81). Although these early findings establish a molecular foundation, no compounds have advanced to preclinical animal efficacy studies. However, progress with analogous RNA methyltransferase targets (e.g., METTL3 inhibitors advancing to clinical trials) provides a promising pathway for optimizing METTL1 inhibitors (82, 83).

Nanotherapeutic approaches: The PAE@5-FUts nanocomplex selectively delivers 5-fluorouracil (5-FU) to CRC cells overexpressing METTL1. By silencing METTL1-induced tsRNA-GlyGCC, it restores 5-FU sensitivity (IC₅₀ reduction from 28 μM to 6 μM) and suppresses JAK1/STAT6 signaling in vivo (84). Although nanotherapies targeting METTL1 demonstrate significant potential in tumor treatment, their clinical translation faces critical challenges: safety requires in-depth evaluation of long-term toxicity risks and impacts on normal tissues (85); delivery efficiency is constrained by tumor microenvironment heterogeneity, necessitating optimization of carrier physicochemical properties (e.g., particle size, surface charge) and production quality (86); tumor-specific targeting demands precise patient stratification and ligand modification (e.g., aptamers or antibodies) to enhance cellular selectivitys (87). Future efforts should prioritize intelligent carrier development (e.g., pH/enzyme-responsive materials) and individualized strategies to address these barriers.

Combination therapies: METTL1 overexpression synergizes with CDK4/6 inhibitors (e.g., abemaciclib) in BRCA by enhancing m⁷G tRNA modification-driven translational activation of GADD45A and RB1, amplifying cell cycle blockade through G₂/M phase arrest (via Cyclin B1/CDK1 suppression) and partial G₁/S modulation (via RB1-E2F inhibition). In vivo studies showed combined therapy with METTL1 overexpression significantly improved tumor suppression compared to monotherapies, correlating with elevated RB1/GADD45A levels and reduced Ki67. These findings position METTL1-mediated tRNA epitranscriptomic regulation as a novel enhancer of CDK4/6 inhibitor efficacy(49).

Although METTL1 has several clinical applications as a therapeutic target, there are significant challenges that need to be addressed. For instance, targeting METTL1 may have important therapeutic benefits on various cancers, particularly those characterized by high METTL1 expression, such as BLCA and HCC (15, 19). Researchers have shown that METTL1 can modulate RNA modifications to improve the efficacy of immunotherapies (88–90). Indeed, METTL1 expression altered response to PD-L1 blockade by modulating immune infiltration (16). Its clinical application requires the identification of precise biomarkers that will help to select patient populations who may benefit from METTL1-targeted therapies. Moreover, the complex RNA modification pathways interact with various cellular processes. This interplay highlights the need to fully understand the potential side effects and broader consequences of inhibiting METTL1 activity (91). Furthermore, clinical trial studies are needed to evaluate their safety and efficacy. Overall, the clinical application of METTL1 is yet to be realized and further investigations are needed to resolve the above challenges.