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Abstract

Gastrointestinal malignancies, which arise from multiple etiological factors, are a global health burden due to their high incidence and mortality rates. Nearly all gastrointestinal cancers present genomic and epigenomic alterations that play a critical role in initiating and driving tumor progression. N6-methyladenosine (m6A) methylation, a key epigenetic modification in eukaryotic messenger RNA (mRNA), is pivotal for regulating various cellular biological processes and influences both the progression and prognosis of diverse diseases. In gastrointestinal cancers, m6A methylation is closely associated with tumor proliferation, invasion, metastasis, and radiosensitivity. This review aims to uncover the translational regulatory mechanisms mediated by m6A methylation in gastrointestinal cancers and to clarify its role in radiotherapy, as well as to identify potential molecular targets for improving the efficacy of radiotherapy in treating gastrointestinal tumors.

Graphical Abstract

Keywords

m6A methylation gastrointestinal cancers radiotherapy epigenetics radioresistance

Introduction

Esophageal, liver, gastric, pancreatic, and colorectal cancers collectively represent major gastrointestinal malignancies. These diseases stem from diverse causal factors and pose a global burden due to their high incidence and mortality.^1,2 Early diagnosis and favorable patient prognosis remain challenging, largely because gastrointestinal cancers often present with subtle symptoms during onset and exhibit aggressive invasion and metastasis.^3-5 Advances in medical technology have enabled the widespread use of precision diagnostic tools, which can identify the exact location and severity of lesions.^6,7 Nearly all gastrointestinal cancers harbor genomic and epigenomic DNA alterations, which—together with microenvironmental factors—are key drivers of tumor initiation and progression.^8-10 Moreover, the pathological characteristics of gastrointestinal cancers play a crucial role in determining/selecting the treatment regimen.¹¹ Thus, deciphering the molecular mechanisms of tumorigenesis is essential for advancing diagnostic and therapeutic strategies.

Epigenetics focuses on reversible, heritable phenotypes that do not involve changes in nuclear DNA sequences.⁸ It encompasses chemical modifications such as DNA/RNA methylation, histone modification, non-coding RNA regulation, and chromatin remodeling. For instance, dysregulation of various non-coding RNAs, including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), has been proven to play crucial roles in gastrointestinal tumorigenesis and progression.^12-14 Among these, m6A methylation is the most prevalent RNA modification, typically localized to coding sequences, 3′ untranslated regions (UTRs), and stop codons.¹⁵ Research has shown that m6A methylation modulates tumor biological behaviors by interfering with mRNA transcription, processing, translation, and metabolism.¹⁶ In gastrointestinal cancers, m6A levels in mRNA are frequently dysregulated, and this dysregulation is closely tied to tumor progression and metastasis. However, the role of m6A in mRNA regulation—particularly in translation—remains controversial. For instance, while some studies suggest m6A methylation generally enhances mRNA translation and stability, others report context-dependent roles where it can also promote decay, leading to debates about its precise and universal function in oncogenic regulation. A comprehensive understanding of m6A methylation mechanisms in gastrointestinal cancers is therefore of great value for clinical oncology practice.

Radiotherapy is a cornerstone of clinical cancer treatment, but radiation-induced sterile inflammation and tissue damage pose major challenges.¹⁷ Emerging evidence indicates that m6A methylation can alter the expression and function of genes involved in DNA repair pathways, thereby influencing the efficiency of repairing radiation-induced damage.¹⁸ For instance, Zhang et al reported that m6A-modified RNAs form RNA-DNA hybrids at double-strand DNA break (DSB) sites, recruiting RAD51 and BRCA1 to these locations and promoting homologous recombination (HR)-mediated repair.¹⁹ In another study, radiation-induced ALKBH5 was found to mediate m6A demethylation of IL-6 mRNA, reducing IL-6 production and alleviating radiation pneumonitis.²⁰ To date, most research on tumor radioresistance and radiation-induced injury has focused on the effects of m6A methylation.^21,22

This review summarizes the role of m6A methylation in translational regulation across all types of gastrointestinal cancers, with a specific focus on its regulatory effects on the radiotherapy response of gastrointestinal tumors—an area critical for improving radiotherapy efficacy.

The Concept of m6A Methylation

RNA modification is a widespread post-transcriptional regulatory mechanism, occurring in mRNA, tRNA, rRNA, snRNA, lncRNA, and other RNA species. m6A methylation targets the 6th nitrogen atom of adenine residues in RNA and is regarded as the most common RNA epigenetic modification. It regulates both coding and non-coding RNAs, with primary modification sites located in the 3′UTR near stop codons.²³ Methylation occurs in both mRNA and lncRNA. m6A methyltransferases (“writers”) catalyze this methylation, while demethylases (“erasers”) remove the methyl groups, restoring adenosine residues. Following m6A methylation, m6A-binding proteins (“readers”) selectively bind to modified sites, regulating the cleavage, transport, translation, transcription, and expression of target mRNAs.²⁴ Therefore, methyltransferases, demethylases, and binding proteins are core mediators of m6A methylation.

The m6A methyltransferase complex is centered on METTL3, METTL14, and WTAP. During methylation, the METTL3-METTL14 heterodimer—formed through their interaction—facilitates the transfer of methyl groups to the 6th nitrogen atom of adenine residues: METTL3 provides the catalytic subunit for this reaction, while METTL14 aids in substrate recognition and methyl group localization.²⁵ WTAP interacts with the METTL3-METTL14 heterodimer, enhancing its delivery efficiency to target mRNAs.²⁶ Additionally, the heterodimer associates with RBM15, KIAA1429, ZC3H13, and HAKAI to participate in methylation; among these, ZC3H13 and RBM15 directly regulate m6A methylation.^27,28 Demethylases mediate the reversible removal of m6A methylations. Clinically relevant demethylases include FTO and ALKB family members (ALKBH3, ALKBH5).²⁹ Reader proteins specifically recognize and bind m6A sites to regulate target mRNA fate. Key families include YTH domain proteins (YTHDF1/2/3, YTHDC1/2), HNRNP proteins (HNRNPA2B1, HNRNPC), and IGF2BP proteins (IGF2BP1/2/3).³⁰

The Roles of m6A Methylation in Gastrointestinal Tumors

Growing evidence links m6A methylation to gastrointestinal cancer progression, including tumorigenesis, metastasis, and angiogenesis. Below is a summary of recent findings on m6A in major gastrointestinal cancers (Table 1).

Table 1.

The Roles of m6A in Gastrointestinal Cancers

Cancer type	m6A regulator	Functions in cancer	Key mechanism (s)	Ref.
Esophageal cancer	METTL3	Promotes proliferation, growth and metastasis	Increases m6A levels of MYC, activates EGR1/Snail signaling via YTHDF3, regulates CEP170 methylation & spindle orientation	^31-33
	YTHDF1	Promotes proliferation	Enhances translation of TINAGL1 via m6A binding	³⁴
	FTO	Promotes proliferation	Reduces m6A of LINC00022, promoting p21 degradation and cell cycle progression	^35,36
	NNMT	Promotes metastasis	Decreases H3K4me3 and m6A modification of E-cadherin	³⁷
Gastric cancer	METTL3	Promotes angiogenesis	Stimulates m6A methylation of HDGF mRNA, recognized by IGF2BP3 to drive angiogenesis	³⁸
	METTL14	Suppresses progression	Regulates the miR-30c-2-3p/AKT1S1 axis to inhibit progression	³⁹
	YTHDF1	Promotes proliferation	Promotes translation of FZD7, leading to hyperactivation of the wnt/β-catenin pathway; mediates lncRNA AC026691.1 degradation	^40,41
	ALKBH5	Suppresses progression/Promotes invasion and metastasis	Modulates PKMYT1 expression; decreases methylation of lncRNA NEAT1; mediates CHAC1 depletion	^42-44
Liver cancer	METTL3/IGF2BP2	Promotes HCC growth	Maintains FEN1 expression	⁴⁵
	METTL3/YTHDF1	Promotes HCC progression/liver metastasis	Represses SOCS2 expression; upregulates GPRC5A expression, activating the mTORC1/p70s6k pathway	^46,47
	METTL14	Suppresses HCC metastasis	Interacts with DGCR8 and positively modulates miR-126 in an m6A-dependent manner	⁴⁸
	YTHDF1	Promotes HCC malignancy	Modulates ATG2A and ATG14 translation to promote autophagy	⁴⁹
	WTAP	Promotes HCC progression	Regulates the hur-ets1-p21/p27 axis.	⁵⁰
	YTHDF2	Suppresses HCC proliferation/immune evasion and angiogenesis	Binds m6A site in EGFR 3′UTR to promote mRNA degradation; modulates ETV5/PD-L1/VEGFA axis	^51,52
Pancreatic cancer	METTL3	Promotes proliferation	Upregulates ID2 expression to control NANOG and SOX2; targets lncRNA MALAT1 to regulate PD-L1; regulates m6A and stability of E2F5	^53-55
	METTL3/IGF2BP3	Promotes proliferation and migration	Regulates spermine synthase m6A methylation	⁵⁶
	METTL14	Promotes proliferation and migration	Targets PERP mRNA	⁵⁷
	METTL16	Suppresses growth and metastasis	Modulates MROH8-TBP-CAPN2 pathway; mediates m6A methylation of DVL2 to suppress wnt/β-catenin signaling	^58,59
	IGF2BP2	Promotes PDAC proliferation and migration	Regulates lncRNA-PACERR	⁶⁰
Colorectal cancer	METTL3	Promotes proliferation/immune suppression/pulmonary metastasis	Induces m6A-GLUT1-mTORC1 axis; regulates m6A-BHLHE41-CXCL1 axis; mediates HMGA1 mRNA; targets m6A-SNAIL-CXCL2 axis to recruit M2-type macrophages	^61-64
	IGF2BP3	Regulates cell cycle and angiogenesis	Regulates CCND1 and VEGF expression and stability	⁶⁵
	YTHDF1	Promotes CRC metastasis	Promotes ARHGEF2 translation and RhoA signaling; promotes P65 translation to upregulate CXCL1	^66,67
	METTL14	Suppresses CRC proliferation and metastasis	Downregulates oncogenic lncRNA XIST	⁶⁸

Esophageal Cancer

Esophageal cancer ranks 7th in global incidence and 6th in cancer-related mortality.⁶⁹ Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, and its growth and metastasis are closely associated with m6A.⁷⁰ Elevated METTL3 expression has been detected in ESCC tumor tissues and is further increased in metastatic lesions.³¹ KAT2A-induced H3K27 acetylation (H3K27ac) at the METTL3 promoter drives METTL3 transcription; METTL3 then enhances m6A methylation of EGR1 mRNA, stabilizing this transcript in a YTHDF3-dependent fashion and activating the EGR1/Snail signaling pathway.³² Additionally, METTL3-mediated m6A methylation of centrosomal proteins (eg, CEP170) regulates spindle orientation and cell division—processes critical for ESCC development.³³ FTO is upregulated in ESCC, and its overexpression reduces m6A levels in the lncRNA LINC00022 transcript. This inhibits LINC00022 degradation via the m6A reader YTHDF2; LINC00022 then binds to p21, promoting its ubiquitination-mediated degradation and accelerating cell-cycle progression and proliferation.³⁵ As an m6A methyltransferase, METTL14 negatively regulates FTO function, thereby inhibiting ESCC progression and improving patient prognosis.³⁶ Notably, several m6A regulators discussed above, such as METTL3 and METTL14, have been implicated in modulating radiation response and ferroptosis in ESCC, offering promise for enhancing radiotherapy efficacy.

Gastric Cancer (GC)

While global GC incidence and mortality are declining,⁷¹ GC remains the 3rd leading cause of cancer-related death in China.⁷² METTL3 is significantly upregulated in GC tissues. P300-mediated H3K27ac at the METTL3 promoter induces its transcription, and METTL3 then promotes m6A methylation of HDGF mRNA. The m6A reader IGF2BP3 recognizes and binds to m6A sites on HDGF mRNA, driving tumor angiogenesis.³⁸ METTL14-mediated m6A methylation of circORC5 suppresses GC progression by regulating the miR-30c-2-3p/AKT1S1 axis.³⁹ Mutated YTHDF1 enhances the translation of the Wnt receptor FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promoting gastric carcinogenesis.⁴⁰ Additionally, PHGDH, a key enzyme in the serine synthesis pathway, is upregulated in drug-resistant GC cells. PHGDH binds to IGF2BP1 in an m6A-dependent manner, stabilizing TCF7L2 mRNA and activating the Wnt/β-catenin pathway to confer multidrug resistance.⁷³ Given the role of m6A in drug resistance and tumor progression, it is plausible that similar mechanisms may also contribute to radioresistance in GC.

Liver Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the 2nd leading cause of cancer-related death globally, with over 700,000 annual deaths.⁷⁴ METTL3 is frequently upregulated in HCC and promotes tumor progression via YTHDF2. For example, METTL3 and YTHDF1 jointly enhance m6A methylation of GPRC5A mRNA, upregulating GPRC5A expression. This activates the mTORC1/p70s6k signaling pathway by recruiting mTORC1 to lysosomes, ultimately promoting liver metastasis.⁴⁶ Hypoxia-inducible factor 1α (HIF-1α) induces YTHDF1 expression. YTHDF1 binds to m6A-modified ATG2A and ATG14 mRNA, enhancing their translation and promoting autophagy and autophagy-related HCC malignancy.⁴⁹ Trimethylated H3K4 and H3K27ac at the YTHDF2 promoter upregulate its expression in HCC. YTHDF1 recognizes m6A methylations in the 5′UTR of ETV5 mRNA, recruiting eukaryotic translation initiation factor 3 subunit B to enhance ETV5 translation. Elevated ETV5 then induces PD-L1 and VEGFA transcription, promoting HCC immune evasion and angiogenesis.⁵¹ WTAP mediates m6A methylation of ETS1, suppressing its post-transcriptional expression. This modulates the G2/M phase of HCC cells via the p21/p27 pathway, driving tumor development.⁵⁰ The m6A demethylase ALKBH5 upregulates TMCO3 expression in HCC. TMCO3 directly activates AKT via the PI3K pathway (with Ser85 phosphorylation being critical), thereby promoting HCC progression.⁷⁵ Interestingly, m6A modifications are also involved in radiation-induced liver injury (RILI) and fibrosis, suggesting a dual role of m6A in both HCC progression and radiotherapy-related complications.

Pancreatic Cancer

Pancreatic cancer is 1 of the most aggressive malignancies, with a 5-year survival rate of ∼5%.⁷⁶ As a key m6A writer, METTL3 post-transcriptionally upregulates ID2 expression in an m6A-YTHDF2-dependent manner, stabilizing ID2 mRNA. ID2 then controls the stemness factors NANOG and SOX2 via the PI3K-AKT pathway, supporting pancreatic cancer growth and stemness maintenance.⁵³ Additionally, METTL3 targets the lncRNA MALAT1 to regulate PD-L1 expression, promoting pancreatic cancer cell viability.⁵⁴ METTL14 overexpression directly targets PERP mRNA (a p53 effector related to PMP-22) via m6A, significantly enhancing pancreatic cancer cell proliferation and migration.⁵⁷ METTL16 overexpression increases MROH8 mRNA stability. MROH8 negatively regulates CAPN2 by promoting TBP degradation, thereby inhibiting pancreatic cancer growth and metastasis.⁵⁸ The lncRNA PACERR binds to the m6A reader IGF2BP2, enhancing the cytoplasmic stability of KLF12 and c-Myc in an m6A-dependent manner. In the nucleus, PACERR interacts with KLF12 and recruits EP300 to increase histone acetylation, promoting pancreatic ductal adenocarcinoma (PDAC) proliferation, invasion, and migration.⁶⁰ The strong association between m6A regulators and PDAC aggressiveness underscores their potential influence on therapeutic resistance, including radiotherapy.

Colorectal Cancer (CRC)

CRC is a leading cause of cancer-related death globally, with rising incidence and mortality among young adults.⁷⁷ METTL3 enhances GLUT1 translation via m6A, promoting glucose uptake and lactate production and activating mTORC1 signaling to drive CRC development.⁶¹ It also upregulates BHLHE41 expression, which induces CXCL1 transcription and enhances myeloid-derived suppressor cell (MDSC) migration, leading to immune suppression.⁶² IGF2BP3 binds to m6A sites in the coding sequence (CDS) of CCND1 mRNA (a G1/S cell-cycle checkpoint gene), reducing CCND1 mRNA stability and promoting S-phase entry and cell proliferation. Additionally, IGF2BP3 regulates VEGF mRNA expression and stability in an m6A-dependent manner, driving angiogenesis in colon cancer.⁶⁵ YTHDF1 binds to m6A sites on ARHGEF2 mRNA, enhancing its translation. This modulates RhoA signaling, cell growth, and metastatic potential, promoting CRC metastasis.⁶⁶ METTL14 expression is negatively correlated with lncRNA XIST and YTHDF2 in CRC tissues. Knocking down METTL14 abolishes XIST m6A methylation and increases XIST expression, while YTHDF1 recognizes m6A-methylated XIST to mediate its degradation.⁶⁸ These m6A-mediated regulatory networks not only drive CRC pathogenesis but may also affect radiotherapy response, potentially influencing radiosensitivity.

The Significance of m6A Methylation to the Radiotherapy of Gastrointestinal Tumors

Radiation directly alters RNA structure, affecting m6A methyltransferase binding and catalytic activity and potentially reducing m6A methylation levels.⁷⁸ Mounting evidence suggests that dynamic changes in m6A methylation offer a new strategy for enhancing tumor radiosensitivity.^79,80 Herein, we summarized recent studies of the significance of m6A methylation to the radiotherapy of gastrointestinal cancers (Table 2).

Table 2.

The Roles of m6A in Modulating the Radiotherapy Response of Gastrointestinal Tumors

Cancer type	m6A regulator	Expression	Key mechanism (s)	Ref.
Esophageal cancer	METTL3	Upregulated	Increases m6A level in the 3′ UTR of SOCS6 mRNA, inhibiting its expression and enhancing radioresistance	⁸¹
	METTL3	Upregulated	Mediates m6A levels in the 3′UTR of SLC7A11, increasing ferroptosis and re-sensitizing radioresistant cells	⁸²
	METTL3	Upregulated	Mediates LNCAROD stabilization, preventing ubiquitin-proteasomal degradation of PARP1, enhancing radioresistance	⁸³
	METTL14	Upregulated	Upregulates m6A methylation of ACSL4 mRNA, accelerating radiation-induced ferroptosis and enhancing radiosensitivity	⁸⁴
Gastric cancer	WTAP	Upregulated	Promotes TGF-β expression and mRNA stability, enhancing radioresistance	⁸⁵
Liver cancer	METTL3/YTHDC1	Upregulated	Recognizes m6A-methylated lncRNA MEG3, reversing miR-20b-mediated inhibition of BNIP2, causing radiation-induced liver injury (RILI)	⁸⁶
Liver cancer	ALKBH5	Upregulated	Demethylates HMGB1 3′ UTR, activating STING-IRF3 signaling, causing RILI; mediates TIRAP mRNA demethylation, decreasing HCC radiosensitivity	^87,88
Pancreatic cancer	METTL3/IGF2BP2	-	Upregulates PLK1 expression, activating the ATR pathway and increasing radiation sensitivity	^89,90
Colorectal cancer	METTL3	Upregulated	Mediates m6A methylation of circ_0124554, inducing LASP1 expression via miR-1184, promoting radioresistance	⁹¹
	ALKBH5/YTHDF2	-	Mediates m6A methylation of circAFF2, inhibiting cullin neddylation and enhancing radiation sensitivity	⁹²
	KIAA1429	Upregulated	Upregulates lncRNA EBLN3P, which competitively binds miR-153-3p, increasing CRC radioresistance	⁹³

Esophageal Cancer

Radiotherapy is a standard treatment for patients with locally advanced or inoperable ESCC.⁹⁴ However, radioresistance limits its efficacy. Therefore, identifying targets to overcome ESCC radioresistance is a key research focus.⁹⁵ m6A-mediated ferroptosis inhibition is closely linked to ESCC radioresistance. METTL3 increases m6A levels in the 3′UTR of SOCS6 mRNA, suppressing SOCS6 expression and promoting radioresistance.⁸¹ Additionally, SOCS2-enhanced SLC7A11 ubiquitination promotes ferroptosis and enhances radiosensitivity,⁹⁶ while the combination of cinobufagin and radiation reduces m6A levels in the SLC7A11 3′UTR (in a METTL3-dependent manner) to increase ferroptosis and re-sensitize radioresistant HCC cells.⁸² Conversely, METTL14 overexpression enhances m6A methylation of ACSL4 mRNA, accelerating radiation-induced ferroptosis and increasing ESCC radiosensitivity.⁸⁴ Specifically, METTL3-mediated m6A methylation of SOCS6 mRNA leads to its suppression, which in turn disinhibits the GPX4 antioxidant pathway, a key guardian against ferroptosis. Conversely, METTL14-mediated m6A methylation of ACSL4 mRNA enhances the production of polyunsaturated fatty acid phospholipids, the substrates for lipid peroxidation, thereby accelerating radiation-induced ferroptosis. METTL3-mediated m6A methylation stabilizes the lncRNA LNCAROD (post-transcriptionally regulated by YTHDC1). LNCAROD prevents PARP1 ubiquitin-proteasomal degradation by facilitating the PARP1-NPM1 interaction, promoting HR-mediated DSB repair and enhancing ESCC radioresistance.⁸³

Liver Cancer

Radiotherapy is vital for the treatment of primary liver cancers (eg, HCC),²⁰ but is limited by radiation-induced liver injury (RILI)—a major complication manifesting as hepatitis, fibrosis, or even liver failure.⁹⁷ The m6A reader YTHDC1 recognizes METTL3-mediated m6A methylation of lncRNA MEG3, modulating RILI.⁸⁶ Irradiation recruits ALKBH5 to demethylate the HMGB1 3′UTR, activating STING-interferon regulatory factor 3 signaling; ALKBH5 deficiency reduces IL-1 production, hepatocyte apoptosis, and post-irradiation liver inflammation.⁸⁷ Additionally, radiation induces ALKBH5 expression in hepatic stellate cells (HSCs), mediating TIRAP mRNA m6A demethylation and activating downstream NF-κB and JNK/Smad2 pathways. This promotes HSC activation, monocyte recruitment, and M2 polarization, forming a positive feedback loop that drives radiation-induced liver fibrosis (RILF) and reduces HCC radiosensitivity.⁸⁸

Colorectal Cancer

Radiotherapy is widely used for CRC (eg, preoperative chemoradiotherapy for locally advanced rectal cancer).⁹⁸ However, radioresistance remains a major challenge.⁹⁹ METTL3-mediated m6A methylation of circ_0124554 promotes CRC progression and radioresistance by interacting with miR-1184 to induce LASP1 expression.⁹¹ ALKBH5 and YTHDF2 jointly mediate m6A methylation of circAFF2. The modified circAFF2 binds to CAND1, enhancing CAND1-Cullin1 interaction and inhibiting Cullin1 neddylation, thereby increasing CRC radiosensitivity.⁹² The m6A methyltransferase KIAA1429 upregulates lncRNA EBLN3P via m6A methylation. EBLN3P competitively binds to miR-153-3p, increasing KIAA1429 expression, reducing ferroptosis, and enhancing CRC radioresistance.⁹³

Gastric Cancer and Pancreatic Cancer

While surgical/endoscopic resection is first-line for GC,¹⁰⁰ adjuvant therapies (eg, radiotherapy) are gaining attention in precision oncology. High expression of the m6A methylase WTAP correlates with poor GC prognosis; WTAP overexpression promotes TGF-β expression and mRNA stability, enhancing chemo- and radioresistance.⁸⁵

Pancreatic adenocarcinoma exhibits strong resistance to all therapies, including radiotherapy.¹⁰¹ Pancreatic adenocarcinoma cells with low METTL3 expression are more sensitive to chemotherapeutics (gemcitabine, 5-fluorouracil, cisplatin) and radiotherapy.⁸⁹ METTL3 directly regulates PLK1 methylation and expression in a cell-cycle-dependent manner; PLK1 3′UTR methylation stabilizes PLK1 via IGF2BP2 binding, maintaining cell-cycle homeostasis. PLK1 demethylation activates the ATR pathway, inducing replication stress-mediated cell death and increasing radiosensitivity.⁹⁰

Conclusion and Prospect

m6A methylation is the most prevalent epitranscriptomic modification in mammalian mRNA, regulating RNA stability, splicing, microRNA processing, and translation to influence diverse physiological and pathological processes.^15,102 Emerging evidence shows that m6A and its regulators modulate cell proliferation, differentiation, and apoptosis, thereby affecting gastrointestinal cancer development and metastasis.^103-105 Identifying m6A-mediated translational regulation in gastrointestinal cancer cells may enable the development of novel therapies—for example, targeting m6A writers, readers, or erasers to disrupt oncogene translation.²³ However, inconsistencies and uncertainties remain. For instance, Ma et al.⁴⁸ reported reduced m6A levels in HCC, while Yang et al.¹⁰⁶ observed the opposite. Even for the same tumor and molecule, conflicting conclusions exist regarding downstream targets and mechanisms,^107,108 highlighting the need for further research to clarify clinically relevant pathways for combination therapy design. These discrepancies may stem from several factors, including tumor heterogeneity (eg, subtypes, stages), cellular context (eg, cancer cells vs stromal cells), methodological differences in m6A detection, and the complex, sometimes opposing, functions of m6A regulators in different signaling networks.

Radiotherapy is widely used for gastrointestinal cancers, but challenges persist: pancreatic cancer exhibits strong radioresistance, while liver cancer is prone to radiation-induced injury.^20,109 Previous studies have linked m6A to radioresistance (eg, via DNA repair activation or apoptosis inhibition),^18,110 making m6A regulators potential radiotherapy targets. While METTL3 depletion increases radiosensitivity in pancreatic, esophageal, and colorectal cancer cells,^81,89,91 the specific mechanisms of m6A in gastrointestinal tumor radiotherapy remain poorly understood and require further exploration.

In conclusion, m6A RNA modification research remains an emerging field. Future methodological advancements, coupled with rigorous scientific validation, will be crucial for clarifying its precise role in gene expression regulation. Understanding the mechanism of m6A-mediated epigenetic regulation in gastrointestinal cancers, as well as exploring key regulator factors involved in the modulation of radiotherapy response of gastrointestinal cancers will be extremely beneficial for revealing novel therapeutic targets to enhance radiosensitivity, optimizing radiation protocols, and developing personalized radiotherapy strategies.

Footnotes

Acknowledgments

We would like to express our gratitude to Ms. Aakriti Verma for her proofreading and language polishing of this paper. We are also grateful to Ms. Xinyi Yang for her kind assistance in preparing the graphic abstract.

ORCID iD

Wentao Hu

Author Contributions

Conceptualization, J.B. and H.B.; Writing—Original Draft Preparation, J.B. and H.B.; Writing—Review and Editing, W.H. and W.C.; Supervision, H.B. and W.C. All authors have read and approved the final version of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by the Anhui Provincial Health Research Project (No. AHWJ2023A20434), the Anhui Provincial Scientific Research Project on Traditional Chinese Medicine Inheritance and Innovation (No. 2024CCCX231), the Scientific Research Project of Bengbu Medical University (No. 2024byzd372), the Open Project of State Key Laboratory of Radiation Medicine and Protection (No. GZK1202228), and the Gusu Talent Program (No. GSWS2022042).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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The Roles and Implications of m6A Methylation in Radiotherapy for Gastrointestinal Tumors

Abstract

Keywords

Introduction

The Concept of m6A Methylation

The Roles of m6A Methylation in Gastrointestinal Tumors

Esophageal Cancer

Gastric Cancer (GC)

Liver Cancer

Pancreatic Cancer

Colorectal Cancer (CRC)

The Significance of m6A Methylation to the Radiotherapy of Gastrointestinal Tumors

Esophageal Cancer

Liver Cancer

Colorectal Cancer

Gastric Cancer and Pancreatic Cancer

Conclusion and Prospect

Footnotes

Acknowledgments

ORCID iD

Author Contributions

Funding

Declaration of Conflicting Interests

References