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Review Open Access

METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review)

  • Authors:
    • Chunlan Pu
    • Huan Hu
    • Hengrui Fan
    • Tao Chen
    • Jiao Tang
  • View Affiliations / Copyright

    Affiliations: Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, P.R. China, Department of Laboratory Medicine, Xindu District People's Hospital, Chengdu, Sichuan 610500, P.R. China
    Copyright: © Pu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 71
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    Published online on: April 21, 2026
       https://doi.org/10.3892/ijo.2026.5884
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Abstract

Esophageal cancer (EC), comprising esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), urgently requires novel targeted therapies. The m6A methyltransferase METTL3 has emerged as a critical epitranscriptomic regulator in gastrointestinal malignancies. In ESCC, METTL3 functions predominantly as an oncogene, driving tumor progression via m6A‑dependent modulation of RNA stability, splicing, and translation across key networks, including NOTCH1, EGR1/Snail and Wnt/β‑catenin. Conversely, hypotheses regarding m6A‑independent functions or direct immune‑checkpoint regulation remain unvalidated in EC. Crucially, METTL3 actively modulates DNA damage repair and radiotherapy resistance, exposing a promising therapeutic vulnerability, although clinical pharmacological development remains nascent. Furthermore, METTL3 biology in EAC remains conspicuously uncharacterized. By strictly stratifying evidence by EC subtype, the present review distinguishes empirically validated mechanisms from premature cross‑cancer extrapolations. Ultimately, a novel conceptual framework that redefines METTL3 not merely as a static oncogene, but as a dynamic, context‑dependent regulatory hub, is proposed. Under therapeutic stress, METTL3 amplifies cellular phenotypic plasticity, systematically orchestrating tumor adaptation and treatment resistance.
View Figures

Figure 1

Schematic overview of the canonical
and non-canonical mechanisms by which METTL3-mediated
m6A modification regulates RNA processing and
translation. The left panel shows the canonical
m6A-dependent mode of regulation. In the nucleus, the
METTL3/METTL14 methyltransferase complex catalyzes m6A
deposition on pre-mRNA, which is subsequently recognized by the
reader protein YTHDC1 to regulate mRNA splicing. After nuclear
export, m6A-modified transcripts in the cytoplasm are
recognized by distinct reader proteins, resulting in different
functional outcomes, including increased mRNA stability mediated by
IGF2BP, mRNA decay mediated by YTHDF2, and enhanced translation.
The right panel illustrates the non-canonical function of
cytoplasmic METTL3. METTL3 may cooperate with eIF3 and PABPC1 to
promote translation of target mRNAs in an m6A-dependent
or m6A-independent manner. These non-canonical
mechanisms have been reported in other tumor types, whereas their
role in ESCC/EAC remains to be fully elucidated. m6A,
N6-methyladenosine; pre-mRNA, precursor mRNA; mRNA,
messenger RNA; YTHDC1, YTH domain containing 1; YTHDF2, YTH
N6-methyladenosine RNA binding protein 2; IGF2BP,
insulin-like growth factor 2 mRNA-binding protein; eIF3, eukaryotic
translation initiation factor 3; PABPC1, poly(A)-binding protein
cytoplasmic 1; ESCC, esophageal squamous cell carcinoma; EAC,
esophageal adenocarcinoma.

Figure 2

Schematic overview of the downstream
molecular network and biological functions regulated by METTL3 in
EC. In the nucleus, the METTL3/METTL14 complex catalyzes
m6A deposition on pre-mRNA, which is recognized by
YTHDC1 to regulate mRNA splicing. After export to the cytoplasm,
m6A-modified transcripts participate in multiple
signaling pathways associated with tumor progression. In ESCC,
METTL3 has been implicated in aerobic glycolysis, EMT, cell
cycle/DDR, malignant progression and therapeutic resistance through
APC/β-catenin/c-Myc/PKM2, EGR1/Snail, FAM135B/Wnt/β-catenin,
NOTCH1, DUXAP8, AMIGO2, ATM/Chk2/γ-H2AX, COL12A1/WASF3/p38 MAPK,
circCREBBP/MYC, PI3K/AKT, IFIT2/IFI27, CASP9/BIRC3 and
LNCAROD/PARP1. The figure also summarizes putative
METTL3-associated immune response-related molecules, including
PIK3CA/AKT, TINAGL1 and PD-L1. Collectively, these METTL3-regulated
pathways contribute to the control of proliferation, apoptosis,
invasion and metastasis in EC cells. m6A,
N6-methyladenosine; pre-mRNA, precursor mRNA; mRNA,
messenger RNA; YTHDC1, YTH domain containing 1; EMT,
epithelial-mesenchymal transition; DDR, DNA damage response; ESCC,
esophageal squamous cell carcinoma; EC, esophageal cancer; DUXAP8,
double homeobox A pseudogene 8; IFI27, interferon alpha-inducible
protein 27; IFIT2, interferon-induced protein with
tetratricopeptide repeats 2; FAM135B, family with sequence
similarity 135 member B; MAPK, mitogen-activated protein kinase;
METTL3, methyltransferase-like 3; MYC, MYC proto-oncogene; PARP1,
poly(ADP-ribose) polymerase 1; PD-L1, programmed death-ligand 1;
PKM2, pyruvate kinase M2; PI3K, phosphoinositide 3-kinase; PIK3CA,
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit
alpha; TINAGL1, tubulointerstitial nephritis antigen-like 1; WASF3,
WAS protein family member 3.

Figure 3

Representative small-molecule METTL3
inhibitors and their reported potency and development status. The
colored boxes in the figure indicate the key binding regions of the
inhibitors to METTL3/14. METTL, methyltransferase-like.

Figure 4

Chemical structures of representative
METTL3/14-targeting proteolysis-targeting chimeras' degraders. AML,
acute myeloid leukemia; METTL, methyltransferase-like.
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Copy and paste a formatted citation
Spandidos Publications style
Pu C, Hu H, Fan H, Chen T and Tang J: METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review). Int J Oncol 68: 71, 2026.
APA
Pu, C., Hu, H., Fan, H., Chen, T., & Tang, J. (2026). METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review). International Journal of Oncology, 68, 71. https://doi.org/10.3892/ijo.2026.5884
MLA
Pu, C., Hu, H., Fan, H., Chen, T., Tang, J."METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review)". International Journal of Oncology 68.6 (2026): 71.
Chicago
Pu, C., Hu, H., Fan, H., Chen, T., Tang, J."METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review)". International Journal of Oncology 68, no. 6 (2026): 71. https://doi.org/10.3892/ijo.2026.5884
Copy and paste a formatted citation
x
Spandidos Publications style
Pu C, Hu H, Fan H, Chen T and Tang J: METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review). Int J Oncol 68: 71, 2026.
APA
Pu, C., Hu, H., Fan, H., Chen, T., & Tang, J. (2026). METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review). International Journal of Oncology, 68, 71. https://doi.org/10.3892/ijo.2026.5884
MLA
Pu, C., Hu, H., Fan, H., Chen, T., Tang, J."METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review)". International Journal of Oncology 68.6 (2026): 71.
Chicago
Pu, C., Hu, H., Fan, H., Chen, T., Tang, J."METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review)". International Journal of Oncology 68, no. 6 (2026): 71. https://doi.org/10.3892/ijo.2026.5884
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