RNA m⁶A modification is a driver and therapeutic target in gastric cancer

Abstract

N6-methyladenosine (m⁶A), the most abundant modification in eukaryotic RNAs, plays a critical role in regulating RNA stability, expression, and translation. Key m⁶A regulators are up- or down-regulated in human gastric cancer tissues, by Helicobacter pylori and transcription factors, and the aberrant expression is associated with poor patient prognosis. Dynamic m⁶A modification, orchestrated by methyltransferases, demethylases, and m⁶A-binding proteins, profoundly impacts gastric cancer tumorigenesis, metastasis, cancer cell stemness, immune evasion, and resistance to chemotherapy, radiotherapy, and immunotherapy. While aberrant m⁶A modifications and the expression levels of its regulatory factors in blood samples are novel biomarkers in gastric cancer patients, therapies targeting m⁶A regulators have emerged as promising approaches for treating the disease. In summary, m⁶A RNA methylation represents a pivotal epitranscriptomic mechanism with significant implications for gastric cancer biology and precision oncology.

Graphical Abstract

RNA m⁶A modification plays a critical role in regulating RNA stability/decay, expression, and translation. m⁶A methyltransferases, demethylases and binding proteins are required for gastric cancer tumorigenesis, metastasis, immune evasion, and resistance to anticancer therapies.

Introduction

Gastric cancer remains a significant global health burden, ranking as the fifth most commonly diagnosed malignancy and the third leading cause of cancer-related mortality worldwide, with over one million new cases annually (Sung et al. 2021). The prognosis for advanced gastric cancer remains poor, with a five-year survival rate below 30% in most regions (Rawla and Barsouk 2019). The high mortality rate is largely attributable to late-stage diagnosis, rapid disease progression, and therapeutic resistance, underscoring the critical need for deeper mechanistic insights and precision therapies.

Epitranscriptomic regulations have emerged as essential modulators of tumour biology, complementing genomic and transcriptomic landscapes in shaping cancer progression. Among the diverse RNA modifications, N6-methyladenosine (m⁶A) represents the most prevalent modification in eukaryotic messenger RNA (mRNA) and non-coding RNAs, influencing RNA splicing, nuclear export, stability, decay and translation into proteins (Zaccara et al. 2019). m⁶A modification is dynamically installed, removed, and interpreted by specific regulatory proteins known as “writers” (methyltransferases), “erasers” (demethylases), and “readers” (m⁶A-binding proteins), forming a reversible and finely tuned layer of gene expression control.

Recent studies have implicated dysregulation of m⁶A modification in various cancers, including gastric cancer, where m⁶A regulators modulate critical pathways involved in tumor initiation, progression, immune evasion, and therapy resistance (Deng et al. 2023; Lan et al. 2021). RNA m⁶A methylation affects key oncogenes and tumour suppressors by regulating RNA splicing, stability and translation, influencing gastric cancer cell proliferation, survival, migration, invasion, metastasis and immune responses (Deng et al. 2023; Lan et al. 2021), highlighting its potential as a diagnostic, prognostic, and therapeutic target.

This review comprehensively summarises current advances in understanding the role of RNA m⁶A methylation in gastric cancer, encompassing its regulatory machinery, detection technologies, biological functions in tumour progression and microenvironment modulation, and its implications in diagnosis, prognosis, therapeutic resistance, and targeted therapies. By integrating mechanistic insights with translational potential, this review aims to provide a detailed reference for researchers and clinicians interested in the epitranscriptomic landscape of gastric cancer and the opportunities it offers for advancing precision oncology in this challenging disease.

Brief overview of RNA m⁶A methylation and demethylation

RNA m⁶A modification is dynamically regulated by three classes of proteins: “writers”, “erasers”, and “readers”. These regulators control the deposition, removal, and recognition of m⁶A marks on mRNAs and noncoding RNAs, influencing RNA splicing, stability, expression, and translation crucial for cancer biology.

m⁶A “writers”. The m⁶A “writers” include the core methyltransferase complex consisting of METTL3, METTL14 (Liu et al. 2014), and WTAP (Ping et al. 2014), along with auxiliary components such as KIAA1429 (VIRMA) (Yue et al. 2018), RBM15/15B (Patil et al. 2016), and ZC3H13 (Knuckles et al. 2018), which deposit m⁶A modifications on target RNAs. METTL3 serves as the catalytic subunit, while METTL14 enhances substrate recognition and RNA binding (Liu et al. 2014). WTAP stabilises the complex and guides its nuclear localisation (Liu et al. 2014; Ping et al. 2014). VIRMA is implicated in site-specific methylation near the 3'-untranslated region (3’-UTR), relevant for transcript stability (Yue et al. 2018), while RBM15/15B recruits the complex to specific sites (Patil et al. 2016) and ZC3H13 facilitates complex anchoring to nuclear speckles and mediates preferential mRNA methylation in 3'-UTR and near stop codon (Knuckles et al. 2018; Yue et al. 2018) (Fig. 1).

Fig. 1.

Brief overview of RNA m⁶A methylation and demethylation. RNA m⁶A modification is dynamically regulated by three classes of proteins: "writers" (METTL3, METTL14, METTL16, WTAP, and auxiliary components VIRMA and RBM15/RBM15B), which deposit m⁶A; "erasers" (FTO, ALKBH5), which remove m⁶A modifications; and "readers" (YTHDF1/2/3, YTHDC1, IGF2BP1/2/3), which recognize m⁶A marks to regulate RNA splicing, stability, export, and translation

m⁶A “erasers”

The m⁶A “erasers” include FTO and ALKBH5, which remove m⁶A modifications, rendering the process reversible (Jia et al. 2011; Zheng et al. 2013). FTO was the first identified m⁶A demethylase and is linked to various biological processes, including RNA splicing, 3'-end processing, mRNA decay, and mRNA translation into proteins (Bartosovic et al. 2017; Yu et al. 2018; Zhao et al. 2014) (Fig. 1). ALKBH5, localised predominantly in the nucleus, has been shown to regulate RNA export, metabolism, and the assembly of mRNA processing factors in nuclear speckles (Zheng et al. 2013). ALKBH5 reduces NANOG and TACC3 mRNA methylation, upregulates NANOG and TACC3 levels, and thereby increases the percentage of cancer stem cells (Shen et al. 2020; Zhang et al. 2016) (Fig. 1).

m⁶A “readers”

m⁶A “readers” recognise and bind to m⁶A-modified RNAs to mediate downstream effects on splicing, export, decay, and translation. These include YTH domain family proteins (YTHDF1/2/3, YTHDC1/2) (Theler et al. 2014; Wang et al. 2015), heterogeneous nuclear ribonucleoproteins (HNRNPC, HNRNPG, HNRNPA2B1) (Alarcon et al. 2015; De Kesel et al. 2025), and IGF2BP1/2/3 (Molina Molina et al. 2025; Müller et al. 2019). YTHDF1 enhances the translation of m⁶A-modified mRNAs, whereas YTHDF2 promotes mRNA decay, ensuring dynamic regulation of gene expression (Hsu et al. 2017; Wang et al. 2014). HNRNPA2B1 binds to m⁶A marks in nuclear transcripts and miRNA transcripts, facilitating alternative splicing and miRNA processing (Alarcon et al. 2015). IGF2BPs stabilise m⁶A-modified transcripts, promoting oncogene expression, including MYC and SOX2 (Huang et al. 2018; Müller et al. 2019). These “readers” integrate m⁶A signals into key pathways, such as Myc, Wnt/β-catenin and PI3K/AKT, impacting tumorigenesis (Fig. 1).

Detection and profiling of m⁶A modification

Accurate detection and quantitative profiling of m⁶A modifications are crucial for elucidating their functional roles in cancer, including gastric cancer. Multiple advanced technologies have been developed to map m⁶A at transcriptome-wide and single-nucleotide resolution, each with strengths and limitations relevant for cancer research.

MeRIP-Seq/m⁶A-Seq and PA-m⁶A-seq

m⁶A RNA immunoprecipitation followed by sequencing (MeRIP-Seq/m⁶A-Seq) remain widely used methods for transcriptome-wide m⁶A mapping (Dominissini et al. 2012; Meyer et al. 2012). The photo-crosslinking-assisted high-resolution transcriptome-wide m⁶A sequencing (PA-m⁶A-seq) also provides excellent insights into m⁶A distribution (Chen et al. 2015). These methods use anti-m⁶A antibodies to immunoprecipitate methylated RNA fragments, followed by next-generation sequencing, which enables the identification of m⁶A peaks across transcripts. However, these methods offer limited resolution (~ 100–200 nt) and may not detect low-abundance m⁶A sites (Fig. 2).

Fig. 2.

Detection and profiling approaches for RNA m⁶A modification. The main approaches for detecting and profiling RNA m⁶A modifications include m⁶A antibody–based sequencing methods, site-specific cleavage and radioactive labeling, single-cell and single-molecule m⁶A profiling, liquid chromatography–tandem mass spectrometry (LC–MS/MS), and nanopore-based m⁶A profiling

miCLIP and SCARLET

m⁶A individual-nucleotide resolution crosslinking and immunoprecipitation (miCLIP) provides single-nucleotide resolution for m⁶A mapping, using UV crosslinking to covalently attach antibodies to RNA, creating mutations or truncations during reverse transcription that identify modification sites precisely (Linder et al. 2015). On the other hand, the site-specific cleavage and radioactive-labelling approach, followed by ligation-assisted extraction and thin-layer chromatography (SCARLET), accurately determines m⁶A status at any RNA site and allows absolute quantification of m⁶A, but is labour-intensive and low-throughput (Liu et al. 2013) (Fig. 2).

Single-cell and single-molecule m⁶A profiling

Single-cell deamination adjacent to RNA modification targets-sequencing (scDART-seq) has recently been developed to identify transcriptome-wide m⁶A sites in single cells. scDART-Seq reveals considerable heterogeneity in the presence and abundance of m⁶A sites across individual cells (Tegowski et al. 2022). Additionally, a microscopy-based platform for single-molecule m⁶A profiling has recently been developed. In this method, RNAs are directly captured from cell lysates onto oligo-dT-coated coverslips, followed by individual m⁶A-immunolabeled transcript sequencing, enabling correlation between single-cell m⁶A modifications and gene expression. Furthermore, single-molecule m⁶A detection using sequential fluorescence in situ hybridization (seqFISH) allows for the correlation of m⁶A levels in individual genes with single-cell phenotypes (Kim et al. 2021) (Fig. 2).

LC–MS/MS

Liquid chromatography-tandem mass spectrometry (LC–MS/MS) provides a quantitative method for measuring global m⁶A levels in RNA samples extracted from cells and tissues (Zheng et al. 2013). While it cannot pinpoint modification sites, it is a reliable tool for global quantification, complementing sequencing-based approaches (Fig. 2).

Nanopore-based m⁶A profiling

Nanopore-based m⁶A profiling refers to approaches that use Oxford Nanopore Technologies RNA sequencing to detect and quantify m⁶A modifications directly from native RNAs (Liu et al. 2019). Examples of nanopore-based m⁶A profiling methods include direct detection of m⁶A from raw nanopore signals through base-calling error features and signal variations (Liu et al. 2019); m⁶Anet, which applies a multiple instance learning strategy to accommodate the absence of read-level modification annotations during site-level model training (Hendra et al. 2022); Xron, an encoder–decoder deep learning basecaller trained on synthetic and lab-generated data (Teng et al. 2024); and Nanocompore, which performs comparative analyses of direct RNA-Seq data across conditions to identify transcriptome-wide differential m⁶A modifications (Leger et al. 2021) (Fig. 2).

Limitations and challenges

Each m⁶A detection method has technical limitations, including antibody specificity in immunoprecipitation-based methods, potential biases introduced during library preparation, the challenge of distinguishing m⁶A from other modifications (e.g., m⁶Am), and, in the case of nanopore-based m⁶A profiling, relatively low sensitivity for low-abundance transcripts. Comprehensive profiling often requires combining multiple methods for validation.

m⁶A “writers” modulate gastric cancer tumorigenesis

METTL3

Despite an early report indicating that METTL3 was downregulated in human gastric cancer tissues (Shimura et al. 2022), recent studies have consistently shown that both METTL3 expression and RNA m⁶A modification levels are significantly upregulated in gastric cancer tissues compared to their normal counterparts and are associated with poorer patient outcomes (Hu et al. 2025; Sun et al. 2020; Wang et al. 2020; Yue et al. 2019; Zang et al. 2024; Zhang et al. 2022a). Helicobacter pylori (H. pylori) infection results in METTL3 gene transcription and overexpression through the NF-κB pathway, leading to m⁶A modification in host gastric epithelial cells (Wang et al. 2025b; Zang et al. 2024). Through negative feedback, m⁶A modification by METTL3 destabilizes LOX-1 mRNA and decreases the expression of LOX-1 protein in host gastric epithelial cells, which is important for H. pylori adhesion and colonization, suggesting that m⁶A modification in host cells provides protection against H. pylori infection (Zeng et al. 2024a). In Epstein-Barr virus (EBV)-associated gastric carcinoma, METTL3 is upregulated in cancer cells overexpressing ebv-circRPMS1, because ebv-circRPMS1 binds to the transcription modulator Sam68 to promote METTL3 gene transcription (Zhang et al. 2022b). In addition, METTL3 gene transcription is upregulated by the histone acetyltransferase p300 in gastric cancer (Wang et al. 2020) (Fig. 3A).

Fig. 3.

m⁶A methylation, m⁶A “writers” and “erasers” modulate gastric cancer tumorigenesis. Helicobacter pylori (H. pylori) infection and transcription factors such as NF-κB, p300, ATF3, and JUN modulate the expression of m⁶A regulatory proteins. m⁶A "writers," including METTL3 (A), METTL14 (B), METTL16 (C), WTAP (D), and VIRMA (E), and "erasers," including FTO (F) and ALKBH5 (G), target mRNAs, lncRNAs, and circRNAs for m⁶A methylation (by "writers") or demethylation (by "erasers"), thereby enhancing or reducing target RNA stability or translation. These processes promote or suppress gastric cancer initiation, cancer cell proliferation, and survival in vitro, as well as tumor progression in vivo

In gastric cancer cells, METTL3 induces m⁶A modification of STAT5A and DEK mRNAs, enhancing their stability and leading to their overexpression. Consequently, the overexpression of STAT5A and DEK promotes gastric cancer cell proliferation and migration in vitro, as well as tumor progression and metastasis in mouse models (Zang et al. 2024; Zhang et al. 2022a) (Fig. 3A).

METTL3 promotes m⁶A methylation of FNTA, SPHK2, and Ras-related RAB27A mRNAs, enhancing their translation and protein expression via YTHDF1. This leads to increased exosome biogenesis; phosphorylation, ubiquitination, and degradation of KLF2 protein; activation of SRC and MEK/ERK signaling pathways; immunosuppression; gastric cancer cell proliferation in vitro; and tumor progression in vivo (Hu et al. 2025; Huo et al. 2021; Li et al. 2025) (Fig. 3A).

BUB1 overexpression promotes gastric cancer cell proliferation, migration, and invasion, and high BUB1 expression levels in tumor tissues are associated with poor patient prognosis. Mechanistically, BUB1 binds to and interacts with METTL3, enhancing the m⁶A modification of TRAF6 mRNA, leading to NF-κB and FGF18 activation (Wang et al. 2024b) (Fig. 3A).

METTL3 induces NDUFA4 mRNA m⁶A modification through the m⁶A reader IGF2BP1 to enhance NDUFA4 mRNA stability and expression in gastric cancer cells, and NDUFA4 promotes cancer cell glycolysis and mitochondrial fission, leading to gastric cancer cell proliferation and tumor progression (Xu et al. 2022).

In addition to interacting with oncogenic mRNAs, METTL3 can also promote gastric cancer tumorigenesis by inducing m⁶A modification of tumor-suppressive mRNAs and reducing their expression. For example, BATF2 binds to p53, enhances its protein stability, and suppresses ERK phosphorylation, thereby inhibiting gastric cancer cell proliferation in vitro and tumor progression and metastasis in vivo. METTL3 binds to BATF2 mRNA, induces its m⁶A modification and mRNA degradation, and downregulates its expression, thereby exerting tumorigenic effects (Xie et al. 2020) (Fig. 3A).

Beyond mRNAs, METTL3 also interacts with long noncoding RNAs (lncRNAs). METTL3 induces m⁶A modification of the lncRNA THAP7-AS1, stabilizing it and upregulating its expression in an IGF2BP1-dependent manner, thereby promoting gastric cancer cell proliferation (Liu et al. 2022a) (Fig. 3A).

In summary, METTL3 is upregulated in gastric cancer and is associated with poorer patient outcomes. METTL3 promotes tumor progression through m⁶A modifications on various mRNAs and lncRNAs, including STAT5A, DEK, FNTA, SPHK2, and THAP7-AS1, enhancing their stability and translation, which boosts cancer cell proliferation. METTL3 also interacts with tumor-suppressive mRNAs like BATF2, downregulating their expression.

METTL14

METTL14 is downregulated by H. pylori through the transcription factor ATF3 in gastric cancer (Cui et al. 2025a; Fan et al. 2022). The loss of METTL14 reduces m⁶A modification of VAMP3 mRNA and circORC5 RNA, leading to their stabilization via IGF2BP2. This, in turn, enhances VAMP3-mediated c-Met recycling. As a result, METTL14 suppresses gastric cancer cell proliferation and metastasis both in vitro and in vivo (Cui et al. 2025a; Fan et al. 2022). Additionally, METTL14 upregulates the expression of the lncRNA lnc-PLCB1 through YTHDF2-mediated m⁶A modification, and lnc-PLCB1 suppresses gastric cancer cell proliferation and migration both in vivo and in vitro (Chang et al. 2024) (Fig. 3B). As such, METTL14 plays a tumor-suppressive role in gastric cancer.

METTL16

METTL16 is highly expressed in human gastric cancer tissues, and elevated METTL16 levels are associated with poor patient prognosis (Wang et al. 2021). METTL16 promotes m⁶A modification of Cyclin D1 mRNA, leading to its stabilization and overexpression, which enhances gastric cancer cell proliferation in vitro and tumor progression in vivo (Wang et al. 2021). In addition, METTL16 plays a key role in cuproptosis—a form of cell death caused by elevated copper levels—by inducing FDX1 mRNA m⁶A modification, stabilization and overexpression. Copper stress enhances METTL16 lactylation at lysine 229 (K229), thereby promoting cuproptosis (Sun et al. 2023) (Fig. 3C).

WTAP

WTAP is significantly overexpressed in human gastric cancer tissues, and its overexpression is associated with advanced disease stage, lymph node metastasis, and poor patient prognosis (Han et al. 2025; Li et al. 2020; Liu and Da 2023). WTAP targets MAP2K6 mRNA for m⁶A modification, leading to MAP2K6 overexpression and m⁶A modification-dependent gastric cancer cell proliferation, migration, and invasion. Importantly, WTAP suppression inhibits tumor growth in vivo (Han et al. 2025). In addition, WTAP binds to AGAP2-AS1 RNA to promote the formation of the METTL3/METTL14/WTAP m⁶A methyltransferase complex, resulting in STAT3 mRNA m⁶A modification and stabilization and STAT3 pathway activation in an m⁶A-dependent manner, which leads to gastric cancer cell proliferation and migration (Nie et al. 2023) (Fig. 3D).

VIRMA

VIRMA, another m⁶A methyltransferase complex protein, is highly expressed in human gastric cancer tissues and its high expression is associated with poor patient prognosis (Ren et al. 2024; Tang et al. 2023). VIRMA promotes FOXM1 mRNA m⁶A modification and stability, leading to gastric cancer cell proliferation (Tang et al. 2023) (Fig. 3E).

m⁶A “erasers” modulate gastric cancer tumorigenesis

FTO

FTO is overexpressed in gastric cancer tissues, and high levels of FTO predict poor patient prognosis (Cheng et al. 2023; He et al. 2025; Shimura et al. 2022; Wu et al. 2024; Zeng et al. 2024b). H. pylori infection upregulates FTO expression in human gastric cancer cells through the transcription factor JUN (Cheng et al. 2023; He et al. 2025), and the transcription factor FOXA2 has also been found to upregulate FTO expression by activating its gene transcription (Yang et al. 2021). FTO causes CD44 mRNA demethylation and upregulation in an m⁶A-dependent manner, thereby promoting gastric epithelial cell malignant transformation (Cheng et al. 2023) (Fig. 3F).

FTO induces m⁶A demethylation of HBEGF mRNA and circFAM192A RNA, suppressing their degradation and facilitating gastric cancer cell proliferation (He et al. 2025; Wu et al. 2024). By interacting with hnRNPU mRNA, FTO decreases its m⁶A modification, resulting in exon 14 skipping of the MET gene and gastric cancer cell proliferation (Jin et al. 2025). In addition, FTO promotes gastric cancer cell proliferation, colony formation, migration, and invasion by targeting SP1 mRNA for m⁶A demethylation, leading to SP1 mRNA stabilization and overexpression, AURKB overexpression, p53 protein dephosphorylation and p38 and ATM protein phosphorylation (Zeng et al. 2024b) (Fig. 3F).

In summary, FTO overexpression results in gastric epithelial cell malignant transformation and cancer cell proliferation by inducing m⁶A demethylation of various RNAs, including CD44, HBEGF, circFAM192A, and SP1.

ALKBH5

Bile acid reflux and consequent CDX2 activation are key factors for the development of gastric intestinal metaplasia, a precursor of gastric cancer (Debruyne et al. 2006). ALKBH5 is upregulated through NF-κB-mediated gene transcription and induces m⁶A demethylation of ZNF333 mRNA, suppressing YTHDF2-dependent ZNF333 mRNA decay. This leads to ZNF333 upregulation and activation of CDX2 in gastric cancer cells (Yue et al. 2021). As ALKBH5 expression is positively associated with ZNF333 and CDX2 expression in human gastric intestinal metaplasia tissues, these data suggest that ALKBH5 promotes the development of gastric intestinal metaplasia (Yue et al. 2021) (Fig. 3G).

m⁶A modifications play a critical role in the adaptation of gastric cancer cells to hypoxia. ALKBH5 expression is significantly upregulated under hypoxic conditions, and ALKBH5 reduces the m⁶A methylation, stability, and expression of target mRNAs, such as CXCL10, leading to gastric cancer cell proliferation (Liu et al. 2025) (Fig. 3G).

ALKBH5 has been reported to be significantly downregulated (Zheng et al. 2025) or upregulated (Fang et al. 2023) in human gastric cancer tissues, with both alterations predicted to correlate with poor patient prognosis. ALKBH5 overexpression activates STAT3 by demethylating m⁶A-modified JAK1 mRNA and upregulating JAK1 expression, resulting in gastric cancer cell proliferation and metastasis both in vitro and in vivo (Fang et al. 2023). In contrast, ALKBH5-mediated m⁶A demethylation of WRAP53 mRNA reduces its stability and translation, suppressing the PI3K/Akt/mTOR signaling pathway and inhibiting gastric cancer cell proliferation, migration, and invasion (Zheng et al. 2025). More research is needed to understand the opposing roles of ALKBH5 in gastric cancer under different contexts (Fig. 3G).

m⁶A “readers” modulate gastric cancer tumorigenesis

YTHDF1

YTHDF1 is upregulated in human gastric cancer tissues compared with adjacent normal tissues, and high levels of YTHDF1 predict poor patient prognosis (Bai et al. 2022). In addition, YTHDF1 is mutated in approximately 7% of human gastric cancer tissues, and YTHDF1 mutation predicts aggressive tumor progression and poor patient prognosis (Pi et al. 2021). YTHDF1 facilitates the translation of Wnt receptor Frizzled7 (FZD7) mRNA into protein in an m⁶A-dependent manner, and mutant YTHDF1 further upregulates FZD7 expression, resulting in activation of the Wnt/β-catenin pathway, gastric cancer cell proliferation in vitro and tumor progression in vivo (Pi et al. 2021) (Table 1).

Table 1.

m⁶A “readers” modulate gastric cancer tumorigenesis

Regulators	Expression in cancer tissues	Functions	References
YTHDF1	Upregulated	YTHDF1 facilitates the translation of FZD7 protein in an m6A-dependent manner, and mutant YTHDF1 further upregulates FZD7 expression, resulting in Wnt/β-catenin pathway activation, gastric cancer cell proliferation in vitro and tumor progression in vivo	(Pi et al. 2021)
YTHDF2	Unknown	YTHDF2 promotes the m6A modification, stability and expression of SRA1 and RASD1 mRNAs, which in turn facilitates NF-κB pathway activation, malignant transformation, gastric cancer cell proliferation, and tumor progression	(Ren et al. 2024; Wang et al. 2025a)
IGF2BP1	Upregulated	IGF2BP1 directly binds to c-Myc mRNA and promotes its m6A modification and stabilization, leading to c-Myc overexpression, gastric cancer cell proliferation in vitro and tumor progression in vivo	(Luo and Lin 2022)
IGF2BP2	Upregulated	IGF2BP2 promotes gastric cancer cell cycle progression and proliferation by binding to the m6A-modified HIF1α mRNA, leading to HIF1α mRNA stabilization and overexpression and enhanced glycolysis	(Zhang et al. 2025)
IGF2BP3	Upregulated	IGF2BP3 promotes gastric cancer cell proliferation and survival in vitro and tumor progression in vivo through inducing NFAT1 mRNA stabilization and translation in an m6A-dependent manner	(Ge et al. 2024)

YTHDF2

H. pylori suppress the function of YTHDF2 (Wang et al. 2025a). YTHDF2 promotes the m⁶A modification, stability and expression of SRA1 and RASD1 mRNAs, which in turn facilitates NF-κB pathway activation, malignant transformation, gastric cancer cell proliferation, and tumor progression (Ren et al. 2024; Wang et al. 2025a) (Table 1).

IGF2BP1

IGF2BP1 is upregulated in human gastric cancer tissues, and its upregulation is associated with poor patient prognosis. Functionally, IGF2BP1 directly binds to c-Myc mRNA, promoting its m⁶A modification and stabilization, which leads to c-Myc overexpression, gastric cancer cell proliferation in vitro and tumor progression in vivo (Luo and Lin 2022) (Table 1).

IGF2BP2

IGF2BP2 is overexpressed in human gastric cancer tissues, and its overexpression predicts poor patient outcomes (Zhang et al. 2025). IGF2BP2 promotes gastric cancer cell cycle progression and proliferation by binding to the m⁶A-modified "GGACU" motif of HIF1α mRNA, leading to HIF1α mRNA stabilization and overexpression and enhanced glycolytic activity (Zhang et al. 2025) (Table 1).

IGF2BP3

IGF2BP3 expression is higher in human gastric cancer tissues than normal tissues and its high expression predicts poor prognosis in patients (Ge et al. 2024). IGF2BP3 is required for gastric cancer cell proliferation and survival in vitro and tumor progression in vivo through inducing NFAT1 mRNA stabilization and translation in an m⁶A-dependent manner (Ge et al. 2024) (Table 1).

m⁶A methylation and m⁶A regulatory proteins modulate gastric cancer metastasis

m⁶A methylation regulates gastric cancer cell epithelial-mesenchymal transition (EMT), invasion and metastasis. HOXA10-mediated activation of the TGFβ/Smad signaling pathway upregulates METTL3 expression, which in turn promotes gastric cancer cell EMT in vitro and metastasis in a mouse model (Song and Zhou 2021; Yue et al. 2019). Mechanistically, METTL3 induces m⁶A modification of HDGF and ZMYM1 mRNAs, enhancing their stability in a manner dependent on the "reader" proteins IGF2BP3 and HuR. HDGF promotes metastasis by enhancing glycolysis in gastric cancer cells and stimulating angiogenesis (Wang et al. 2020), whereas ZMYM1 facilitates EMT and metastasis by suppressing E-cadherin expression (Yue et al. 2019) (Fig. 4A).

Fig. 4.

m⁶A methylation and m⁶A regulatory proteins modulate gastric cancer metastasis. m⁶A "writers," including METTL3 (A), METTL14, WTAP, and VIRMA (B), and "erasers," including FTO and ALKBH5 (C), target mRNAs involved in cancer cell invasion, epithelial-mesenchymal transition, and metastasis for m⁶A methylation or demethylation, thereby enhancing or reducing target mRNA stabilization or translation. These processes, facilitated by "readers," promote or suppress gastric cancer cell invasion, epithelial-mesenchymal transition, and metastasis

PBX1, MIB1, CENPF and RPRD1B are highly expressed in gastric cancer metastasis tumors, and enhance gastric cancer cell EMT and metastasis (Liu et al. 2022b; Xu et al. 2024, 2023a). Importantly, METTL3 stabilizes MIB1, CENPF, PBX1 and RPRD1B mRNAs and causes their overexpression in a m⁶A-dependen manner, and METTL3 knockdown reduces gastric cancer lymph node and lung metastasis in vivo (Jia et al. 2022; Liu et al. 2022b; Xu et al. 2024, 2023a) (Fig. 4A). In addition, through promoting LHPP mRNA m⁶A modification, stabilization and overexpression, METTL14 reduces GSK3β phosphorylation, glycolysis, and gastric cancer cell invasion and metastasis both in vitro and in vivo (Lin et al. 2022) (Fig. 4B).

TGFβ and RASD1 are known to promote and suppress tumor metastasis, respectively (Tanaka et al. 2021; Tang et al. 2019). WTAP enhances TGFβ mRNA stability and expression, thereby promoting gastric cancer cell EMT and migration (Liu and Da 2023), meanwhile, VIRMA facilitates gastric cancer cell migration and invasion in vitro, as well as tumor metastasis in vivo, by promoting m⁶A modification, destabilization, and downregulation of RASD1 mRNA in an YTHDF2-dependent manner (Ren et al. 2024) (Fig. 4B).

The involvement of FTO in gastric cancer metastasis remains debated. FTO is overexpressed in gastric cancer tissues, particularly in gastric cancer liver metastasis tissues. It causes demethylation and subsequent degradation of caveolin-1 mRNA, leading to enhanced gastric cancer cell proliferation and metastasis (Zhou et al. 2022). In contrast, in Epstein-Barr virus-associated gastric cancer, the Myc oncoprotein activates FTO gene transcription (Xu et al. 2023b). FTO, in turn, reduces the aggressiveness and metastasis of Epstein-Barr virus-associated gastric cancer by decreasing the m⁶A modification, stability, and expression of the FOS mRNA. m⁶A-modified FOS mRNA is recognized by IGF2BP1/2, which enhances its stability (Xu et al. 2023b) (Fig. 4C).

Low levels of ALKBH5 in human gastric cancer tissues predict lymph node and distal metastasis. ALKBH5 knockdown promotes gastric cancer cell metastasis by causing PKMYT1 mRNA m⁶A methylation, leading to PKMYT1 mRNA stabilization and upregulation, while IGF2BP3 stabilizes PKMYT1 mRNA through an m⁶A modification-dependent mechanism (Hu et al. 2022) (Fig. 4C).

m⁶A methylation and m⁶A regulatory proteins modulate gastric cancer tumor microenvironment and immune responses

Emerging evidence indicates that m⁶A modification and m⁶A regulatory proteins modulate the tumour microenvironment (TME) and immune responses in gastric cancer. Analyses of m⁶A modification patterns in 1938 gastric cancer tissues reveal correlation with three immune phenotypes: immune-excluded, immune-inflamed and immune-desert phenotypes (Zhang et al. 2020). Low levels of m⁶A modification are associated with immune activation and an inflamed TME, while high levels of m⁶A correspond with stroma activation, less immune infiltration and an immune-exclusion TME. Low levels of m⁶A modification also correlate with augmented neoantigen load and better response to anti-PD-1/L1 immunotherapy (Zhang et al. 2020) (Table 2) (Fig. 5A).

Table 2.

m⁶A methylation and m⁶A regulatory proteins modulate gastric cancer tumor microenvironment and immune responses

Regulators	Targets	Functions	References
m6A level	Immune response	High levels of m6A modification correlate with stroma activation, less immune infiltration, and an immune-exclusion tumor microenvironment. Low levels of m6A modification correlate with augmented neoantigen load and better response to anti-PD-1/L1 immunotherapy.	(Zhang et al. 2020)
METTL3	Vγ9Vδ2T cells	METTL3 interacts with exosomal THBS1 to induce m6A methylation of mRNAs involved in the RIG-I-like receptor signaling pathway in Vγ9Vδ2 T cells, leading to increased mRNA stability and activation of the pathway in an m6A modification-dependent manner, as well as immunotherapy resistance.	(Li et al. 2023)
FTO	M2 macrophage polarization	FTO induces NNMT mRNA m6A demethylation in cancer-associated fibroblasts, leading to NNMT overexpression, M2 macrophage polarization, and gastric cancer progression in mice.	(Mak et al. 2024)
ALKBH5	CD8⁺ T cells	ALKBH5 decreases CD58 expression by inducing CD58 mRNA m6A demethylation in gastric cancer cells, thereby suppressing CD8⁺ T cell cytotoxicity.	(Suo et al. 2024)
YTHDF1	IFNγ signaling, regulatory T cells, dendritic cells, CD4⁺ and CD8⁺ T cells	YTHDF1 represses IFNγ signaling by enhancing IRF1 mRNA m6A modification, promotes the metabolism and homeostasis of immunosuppressive regulatory T cells in an m6A-dependent manner, reduces the recruitment of mature dendritic cells, decreases interleukin-12 secretion, lowers the infiltration of CD4⁺ and CD8⁺ T cells, and thereby suppresses tumor growth.	(Bai et al. 2022; Jang et al. 2025; Wang et al. 2023)
IGF2BP1	T-cell immunity	IGF2BP1 induces PD-L1 mRNA stabilization and overexpression by promoting its 3'-UTR m6A modification, suppressing antitumor T cell immunity in vitro and in vivo.	(Jiang et al. 2024)
IGF2BP2	Mesenchymal stem cells	IGF2BP2 binds to and stabilizes CSF2 mRNA in an m6A-dependent manner in gastric cancer mesenchymal stem cells, leading to CSF2 overexpression. Elevated CSF2 levels reprogram normal mesenchymal stem cells into cancer-promoting mesenchymal stem cells, which secrete pro-inflammatory factors and promote gastric cancer cell proliferation and migration.	(Ji et al. 2023)
IGF2BP3	CD8+ T cells	IGF2BP3 binds to LDHA mRNA m6A site and enhances its mRNA stability, promoting lactate accumulation and suppressing the antitumor immunity of CD8+ T cells.	(Lin et al. 2024)

Fig. 5.

m⁶A methylation and m⁶A regulatory proteins modulate immune responses and promote anticancer therapy resistance. m⁶A methylation “writers”, “erasers” and “readers” regulate immune responses and augment gastric cancer cell resistance to immunotherapy, chemotherapy and radiotherapy

Gastric cancer cell-derived exosomal THBS1 interacts with METTL3 to induce m⁶A methylation of mRNAs involved in the RIG-I-like receptor signaling pathway in Vγ9Vδ2 T cells, leading to increased mRNA stability and activation of the pathway in an m⁶A modification-dependent manner (Li et al. 2023). Exosomal THBS1 thereby promotes the cytotoxicity of Vγ9Vδ2 T cells against gastric cancer cells, enhances the production of TNFα, IFNγ, and granzyme B in vitro, and increases gastric cancer cell killing by Vγ9Vδ2 T cells in vivo (Li et al. 2023). METTL3 is therefore implicated in immunotherapy resistance through its interaction with exosomal THBS1 in Vγ9Vδ2 T cells (Li et al. 2023). In addition, WTAP upregulates immunosuppressive mRNA m⁶A modification and expression, thereby causing immunosuppression (Chen et al. 2025a) (Table 2) (Fig. 5A).

FTO binds to NNMT mRNA and induces m⁶A demethylation, leading to NNMT overexpression in CAFs. Knockdown of FTO or NNMT in CAFs suppresses M2 macrophage polarization and inhibits gastric cancer progression in mice. These findings suggest that FTO promotes M2 macrophage polarization by demethylating NNMT mRNA in CAFs, thereby contributing to gastric cancer progression (Mak et al. 2024) (Table 2) (Fig. 5A). In addition, ALKBH5 decreases CD58 expression in gastric cancer cells by inducing CD58 mRNA m⁶A demethylation, thereby suppressing the cytotoxicity of CD8⁺ T cells. In human gastric cancer tissues, ALKBH5 expression is negatively correlated with CD58 expression (Suo et al. 2024) (Table 2).

High levels of YTHDF1 in gastric cancer tissues are linked to immune suppression and poorer patient survival (Jang et al. 2025). YTHDF1 inhibits immune responses by targeting IRF1 mRNA for m⁶A modification, thereby reducing IRF1 mRNA stability and expression and repressing IFNγ signaling. In mice, YTHDF1 depletion enhances lymphocyte infiltration into tumors, promotes IFNγ signaling, and suppresses tumor growth (Jang et al. 2025). In addition, YTHDF1 promotes the metabolism and homeostasis of immunosuppressive regulatory T cells in an m⁶A-dependent manner (Wang et al. 2023), and YTHDF1 reduces the recruitment of mature dendritic cells, decreases interleukin-12 secretion, and inhibits the infiltration of CD4⁺ and CD8⁺ T cells, leading to immune suppression (Bai et al. 2022) (Table 2) (Fig. 5B).

IGF2BP1 induces PD-L1 mRNA stabilization and overexpression by promoting its 3'-UTR m⁶A modification, suppressing antitumor T-cell immunity in vitro and in vivo (Jiang et al. 2024). IGF2BP2 binds to and stabilizes CSF2 mRNA in an m⁶A-dependent manner in gastric cancer mesenchymal stem cells, leading to CSF2 overexpression. Elevated CSF2 levels reprogram normal mesenchymal stem cells into cancer-promoting mesenchymal stem cells, which secrete pro-inflammatory factors and promote gastric cancer cell proliferation and migration (Ji et al. 2023). In addition, IGF2BP3 binds to the m⁶A site on LDHA mRNA and enhances its stability, promoting lactate accumulation and suppressing the antitumor immunity of CD8⁺ T cells (Lin et al. 2024) (Table 2) (Fig. 5B).

m⁶A methylation and m⁶A regulatory proteins promote anticancer therapy resistance

METTL3 interacts with ABL mRNA to induce m⁶A modification and thereby maintain its stability, and with the m⁶A reader hnRNPA2B1 to stabilize RPRD1B mRNA and the lncRNA NEAT1 in an m⁶A-dependent manner, thereby enhancing gastric cancer cell stemness via the Wnt/β-catenin signaling pathway and rendering gastric cancer cells resistant to apoptosis and chemotherapeutic agents such as 5-fluorouracil, cisplatin, and paclitaxel (Wang et al. 2024a, 2022) (Table 3) (Fig. 5A).

Table 3.

m⁶A methylation and m⁶A regulatory proteins promote anticancer therapy resistance

Regulators	Therapy resistance	Mechanisms	References
METTL3	5‐fluorouracil, cisplatin, & paclitaxel	METTL3 interacts with hnRNPA2B1 to induce NEAT1 and RPRD1B RNA m6A modification and stability, thereby enhancing gastric cancer cell stemness through the Wnt/β-catenin signaling pathway and promoting resistance to apoptosis.	(Wang et al. 2024a; Wang et al. 2022)
METTL3	Cisplatin	METTL3 induces m6A modification and stabilization of SUV39H2 mRNA in an IGF2BP2-dependent manner, suppressing DUSP6 gene transcription and thereby promoting ATM phosphorylation.	(Yang et al. 2023)
METTL3	Oxaliplatin	METTL3 promotes PARP1 mRNA stability through YTHDF1-mediated m6A modification, leading to DNA damage repair after oxaliplatin treatment in CD133⁺ gastric cancer stem cells.	(Li et al. 2022)
WTAP	Radiotherapy, cisplatin & cyclophosphamide	WTAP enhances TGFβ mRNA m6A modification, stability and expression, thereby promoting gastric cancer cell EMT, migration, and therapy resistance.	(Liu and Da 2023)
VIRMA	Oxaliplatin	VIRMA promotes FOXM1 mRNA m6A modification and stability, leading to therapy resistance.	(Tang et al. 2023)
FTO	Cisplatin	FTO upregulates ULK1 expression in an m6A demethylation-dependent and YTHDF2-mediated manner. FTO knockdown sensitizes gastric cancer cells to cisplatin therapy by suppressing ULK1-mediated autophagy.	(Zhang et al. 2022c)
ALKBH5	Cisplatin	ALKBH5 induces m6A demethylation and destabilization of CHAC1 mRNA, thereby reducing CHAC1 expression, decreasing cisplatin-mediated oxidative stress, and conferring resistance.	(Chen et al. 2023)
YTHDC1	Cisplatin	YTHDC1 enhances the stability of m6A-modified FAM120A mRNA, leading to FAM120A overexpression and inhibition of ferroptosis.	(Niu et al. 2024)
YTHDF1	Cisplatin	YTHDF1 promotes the translation of the drug-resistance proteins BAIAP2L2 and ANXA4 by enhancing their mRNA m6A modification.	(Liao et al. 2025)
IGF2BP1	Adriamycin, vincristine, cisplatin & fluorouracil	IGF2BP1 induces TCF7L2 mRNA m6A modification and stabilization, leading to PHGDH gene transcription and overexpression and treatment resistance.	(Chen et al. 2025b)
IGF2BP2	Radiotherapy	IGF2BP2 promotes HIF1α mRNA m6A modification and m6A-dependent HIF1α mRNA stabilization, overexpression and glycolysis.	(Zhang et al. 2025)
IGF2BP2	Anti-PD-1 therapy	IGF2BP2 facilitates m6A methylation, stabilization, and overexpression of CXCL2 mRNA, leading to gastric cancer cell resistance to anti-PD-1 therapy.	(You et al. 2025)

METTL3 induces m⁶A modification of SUV39H2, thereby promoting its mRNA stability in an IGF2BP2-dependent manner. Upregulation of SUV39H2 enhances ATM phosphorylation by suppressing DUSP6 gene transcription, leading to gastric cancer cell resistance to cisplatin treatment (Yang et al. 2023). In addition, METTL3 promotes resistance to oxaliplatin. CD133⁺ stem cell-like cells represent a major subpopulation of oxaliplatin-resistant gastric cancer cells (Li et al. 2022). These cells exhibit elevated METTL3 expression, which enhances PARP1 mRNA stability through YTHDF1-mediated m⁶A modification in the 3′-UTR of PARP1 mRNA, facilitating effective DNA damage repair following oxaliplatin treatment (Li et al. 2022). These findings suggest that METTL3 contributes to oxaliplatin resistance in CD133⁺ gastric cancer stem cells by promoting m⁶A modification and stabilization of PARP1 mRNA (Li et al. 2022) (Table 3) (Fig. 5A).

WTAP, a METTL3 functional partner, enhances TGFβ mRNA stability and expression, thereby promoting gastric cancer cell EMT, migration, and resistance to radiotherapy and chemotherapy agents such as cisplatin and cyclophosphamide (Liu and Da 2023). VIRMA, another METTL3 functional partner, promotes FOXM1 mRNA m⁶A modification and stability, leading to gastric cancer cell resistance to oxaliplatin treatment (Tang et al. 2023) (Table 3) (Fig. 5A).

The m⁶A “eraser” FTO is significantly overexpressed in cisplatin-resistant gastric cancer cells. Functionally, FTO upregulates ULK1 expression in an m⁶A-dependent and YTHDF2-mediated manner. FTO knockdown sensitizes gastric cancer cells to cisplatin therapy in vitro and in vivo by suppressing ULK1-mediated autophagy (Zhang et al. 2022c) (Table 3) (Fig. 5A).

The oxidative stress regulator CHAC1 plays an important role in chemotherapy response. The m⁶A “eraser” ALKBH5 induces m⁶A demethylation and destabilization of CHAC1 mRNA, thereby reducing CHAC1 expression, decreasing cisplatin-mediated oxidative stress and conferring cisplatin resistance in gastric cancer cells (Chen et al. 2023) (Table 3).

YTHDC1 enhances the stability of m⁶A-modified FAM120A mRNA, leading to FAM120A overexpression, which contributes to resistance to cisplatin treatment through the inhibition of ferroptosis (Niu et al. 2024). Meanwhile, BAIAP2L2 contributes to cisplatin resistance through extracellular vesicle proteins, such as ANXA4, and YTHDF1 promotes the translation and overexpression of BAIAP2L2 and ANXA4 proteins by enhancing their mRNA m⁶A modification (Liao et al. 2025) (Fig. 5B).

IGF2BP1 interacts with the PHGDH protein to induce m⁶A modification, stabilization, and overexpression of TCF7L2 mRNA in an m⁶A-dependent manner. TCF7L2, in turn, promotes PHGDH gene transcription and overexpression, leading to gastric cancer cell resistance to multiple chemotherapy agents, including adriamycin, vincristine, cisplatin, and fluorouracil (Chen et al. 2025b). IGF2BP2 promotes gastric cancer radiotherapy resistance through m⁶A-dependent regulation of HIF1α by binding to the m⁶A-modified "GGACU" motif of HIF1α mRNA, resulting in HIF1α mRNA stabilization, overexpression, and enhanced glycolytic activity (Zhang et al. 2025). In addition, IGF2BP2 facilitates CXCL2 mRNA m⁶A methylation, stabilization and overexpression, contributing to gastric cancer cell resistance to anti-PD-1 therapy (You et al. 2025) (Table 3) (Fig. 5B).

m⁶A methylation and m⁶A regulatory proteins as biomarkers and cancer therapy targets in gastric cancer

As discussed earlier, aberrant m⁶A modification and dysregulated expression of m⁶A regulatory proteins in human gastric cancer tissues are associated with tumor progression, metastasis, therapy resistance, and poor prognosis, highlighting their potential as biomarkers for gastric cancer management.

RNA m⁶A levels in peripheral blood samples are elevated in gastric cancer patients compared to those with benign gastric disease and healthy controls, and the levels increase further when the primary cancer metastasizes (Ge et al. 2020). In addition, ALKBH5 and FTO mRNAs are downregulated in blood samples from the gastric cancer patient group compared to those from the healthy control group. Therefore, m⁶A, ALKBH5, and FTO levels in peripheral blood RNA samples are promising biomarkers for gastric cancer (Ge et al. 2020).

METTL3-mediated m⁶A modification at the A879 locus of pri-miR-17–92 promotes its processing into the miR-17–92 cluster, which subsequently activates the AKT/mTOR pathway. Therefore, METTL3-overexpressing gastric cancer tumors exhibit high sensitivity to treatment with mTOR inhibitors, including everolimus (Sun et al. 2020). These data suggest that everolimus is potentially an efficacious therapeutic agent for METTL3-overexpressing gastric cancer.

Targeting m⁶A regulatory proteins presents a novel strategy for gastric cancer treatment. Small-molecule inhibitors against m⁶A “writers”, “erasers”, and “readers” are under development, aiming to modulate m⁶A levels and restore normal RNA methylation profile in cancer cells. While STC-15, the METTL3 inhibitor currently in clinical trials, has not been tested in gastric cancer, KH12—a proteolysis-targeting chimera (PROTAC) that targets METTL3—induces METTL3 protein degradation with a half-maximal degradation concentration of 220 nM. KH12 significantly inhibits gastric cancer cell proliferation in an m⁶A-independent manner (Hwang et al. 2024).

Resistance to anti-PD-1 immunotherapy remains a significant challenge in the treatment of gastric cancer. In human gastric cancer tissues, METTL3 expression negatively correlates with PD-L1 and YTHDF2 levels (Fang et al. 2025). Mechanistically, METTL3 induces m⁶A modification of PD-L1 mRNA, leading to YTHDF2-dependent degradation of PD-L1 mRNA. Inhibition of METTL3 using the selective inhibitor STM2457 significantly upregulates PD-L1 expression and enhances the anticancer efficacy of PD-1 monoclonal antibodies in a mouse model of human gastric cancer (Fang et al. 2025). Additionally, METTL3 suppression in gastric cancer cells promotes T cell migration and cytotoxicity. These findings identify METTL3 inhibitors as promising agents that modulate the tumor microenvironment to improve immunotherapy outcomes (Fang et al. 2025).

The oxetanyl class of FTO inhibitors, including FTO-43, increases m⁶A modification levels in a manner comparable to FTO knockdown in gastric cancer cells. This class also exhibits potent effects in inhibiting gastric cancer cell proliferation, with potency similar to that of the chemotherapeutic agent 5-fluorouracil (Huff et al. 2022). Additionally, the FTO inhibitor meclofenamic acid suppresses gastric cancer cell proliferation in vitro and tumor progression in vivo (Jin et al. 2025).

Small extracellular vesicles engineered with high CD47 expression and cyclic arginine-glycine-aspartic acid modification have been developed to effectively deliver siRNAs targeting YTHDF1. These vesicles deplete YTHDF1 expression, stimulate cytotoxic T cell responses, and suppress gastric cancer progression and metastasis by upregulating IFNγ receptor 1 and inhibiting the m⁶A-dependent translation of frizzled7 mRNA (You et al. 2023). This nanoplatform presents a novel strategy to inhibit epitranscriptomic regulators, thereby enhancing immunotherapy and anticancer efficacy. In addition, the natural product Baicalin suppresses the interaction between the IGF2BP3 protein and mRNAs, leading to reduction in mRNA m⁶A modification and expression (Cui et al. 2025b); and multisite deactivated RfxCas13d (dCasRx)-based m⁶A editor modifies m⁶A methylation at target mRNAs and thereby exerts anticancer effects in vitro and in mouse models (Ying et al. 2024).

Conclusion and future perspectives

Gastric cancer continues to pose a major clinical challenge due to its late-stage diagnosis, aggressive nature, and resistance to multimodality therapies. In recent years, the emergence of epitranscriptomic regulation, particularly m⁶A RNA methylation, has added a new dimension to our understanding of tumor biology. The complex and dynamic regulation of m⁶A by "writers," "erasers," and "readers" affects RNA stability and translation, thereby influencing key cancer hallmarks such as cell proliferation, invasion, metastasis, immune evasion, and therapeutic resistance. Notably, m⁶A regulators have been shown to play oncogenic or tumor-suppressive roles depending on cellular context.

Recent advances in detection technologies, such as MeRIP-seq, miCLIP, and single-cell approaches like scDART-seq, have allowed for more precise mapping of m⁶A modifications and revealed considerable heterogeneity in their distribution across tissue subtypes and cell subpopulations. However, challenges remain in understanding the spatial and temporal dynamics of m⁶A modifications in tumors. The context-dependent effects of m⁶A regulators—such as the dual roles of METTL14, ALKBH5, and FTO—necessitate further functional studies using sophisticated models, including patient-derived organoids, xenografts, and spatial transcriptomic platforms. A better understanding of these context-specific effects is essential to avoid unintended consequences of targeting these pathways.

Therapy resistance remains one of the most compelling reasons to explore m⁶A modifications in gastric cancer. Studies have shown that m⁶A dysregulation contributes to chemotherapy, radiotherapy and immunotherapy resistance by regulating transcript stability or translation and thereby promoting cancer cell apoptosis resistance, stemness, EMT, DNA repair, and immune suppression. m⁶A “writers”, “erasers”, and “readers”, such as METTL3, FTO, ALKBH5, YTHDFs, and IGF2BPs, stabilize or destabilize transcripts involved in survival pathways, stemness and immune response, thereby reducing the efficacy of therapeutic interventions. Thus, targeting the m⁶A machinery could enhance treatment response and overcome resistance mechanisms.

Promising preclinical studies of m⁶A-targeting agents—including METTL3 inhibitors (e.g., STC-15, STM2457, KH12) and FTO inhibitors (e.g., meclofenamic acid, FTO-43)—offer hope for clinical translation. Future work should prioritize the evaluation of potent and safe small-molecule inhibitors of m⁶A regulators, such as STC-15, in in vivo models and early-phase clinical trials. Additionally, the development of predictive biomarkers based on m⁶A regulator expression or global m⁶A levels in patient tumors and blood samples may help identify responders and monitor therapeutic efficacy. Strategies that combine m⁶A modulation with chemotherapy, radiotherapy, or immunotherapy hold significant potential, particularly in resistant or recurrent cases.

In summary, integrating m⁶A profiling with genomic, transcriptomic, and immunologic datasets will be crucial for realizing the full potential of precision oncology in gastric cancer. Advances in spatial and single-cell technologies will further enable researchers to map m⁶A-driven cellular states within tumor cells and their microenvironment. As m⁶A dysregulation contributes to resistance against chemotherapy, radiotherapy, and immunotherapy, targeting the m⁶A machinery offers a promising strategy to enhance treatment efficacy. Preclinical studies on inhibitors of m⁶A regulators, such as METTL3 and FTO, show potential for clinical translation. Future efforts should focus on refining small-molecule inhibitors, developing predictive biomarkers, and combining m⁶A modulation with existing therapies to overcome resistance and improve patient outcomes. Ultimately, harnessing the m⁶A epitranscriptome not only promises to deepen our understanding of gastric cancer biology but also opens new avenues for more effective and personalized therapeutic approaches.

Author contributions

Qingjuan Chen and Tao Liu designed this study. Qingjuan Chen, Dezhi Li and Tao Liu drafted the initial manuscript, figures and tables. Qingjuan Chen and Hongzhao Lu revised the manuscript, figures and tables. All authors approved the manuscript.

Funding

This research was supported by the Natural Science Basic Research Program of Shaanxi Province (ID: 2024JC-YBMS-756), the Shaanxi Provincial Key Clinical Specialty Construction Project Fund and Genertec Medical Research Fund (ID: TYYLKYJJ-2023–011).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

This study did not include any studies with human participants or animals.

Clinical trial number

Not applicable.

Competing interests

The authors declare no competing interests.