Inhibiting METTL3 synergizes with Notch blockade to treat ESCC by targeting cancer stemness via m6A-JAG2

  • J Gastroenterol. 2026 Jun 11. doi: 10.1007/s00535-026-02456-8.
Jingjing Duan  #  1 ,  Yingying Jin  #  1 ,  Yue Chen  1 ,  Yinghui Shi  1 ,  Haotian Wang  2 ,  Ming Bai  1 ,  Feixue Wang  1 ,  Yuchong Yang  1 ,  Shaohua Ge  1 ,  Min Zhu  3 ,  Yi Ba  4 ,  Zhongyi Fan  5 ,  Ting Deng  6
Affiliations
  • 1. Department of Gastrointestinal Medical Oncology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan huxi Road, Tianjin, 300060, China.
  • 2. Department of Breast Medical Oncology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan huxi Road, Tianjin, 300060, China.
  • 3. College of Computer Science, Sichuan University, Chengdu, 610065, China.
  • 4. Department of Medical Oncology, Department of Cancer Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100032, China. [email protected].
  • 5. Department of Biotherapy Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, 518112, Guangdong, China. [email protected].
  • 6. Department of Gastrointestinal Medical Oncology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan huxi Road, Tianjin, 300060, China. [email protected].
  • # Contributed equally.
PMID: 42274788 DOI: 10.1007/s00535-026-02456-8
Abstract

Background: Esophageal squamous cell carcinoma (ESCC) remains a therapeutic challenge, characterized by poor prognosis and limited treatments. Despite the established role of Cancer stemness in progression and resistance, current stemness-targeting strategies, including Notch pathway inhibition, have shown suboptimal clinical efficacy. This study investigates the mechanistic role of METTL3-mediated m6A modification in ESCC stemness regulation and explores the therapeutic potential of combining METTL3 inhibitors with Notch blockade.

Methods: We integrated multi-omics Sequencing with functional validation. The METTL3/JAG2/Notch axis was systematically investigated using in vitro assays and in vivo xenograft models. Molecular mechanisms were elucidated through m6A-RNA immunoprecipitation, RNA stability assays, and exosome characterization.

Results: METTL3 was significantly upregulated in ESCC and correlated with poor patient outcomes. Functionally, METTL3 enhanced ESCC cell proliferation, migration, and stemness maintenance through m6A-dependent regulation. Mechanistically, METTL3 catalyzed m6A modification on JAG2 mRNA, which was recognized and stabilized by IGF2BP2, leading to Notch pathway activation and upregulation of stemness markers (SOX9 and CD44). JAG2 mediated intercellular communication via both direct cell-cell contact and exosome-mediated signaling, promoting angiogenesis. Genetic ablation of JAG2 suppressed METTL3-driven tumor progression in vitro and in vivo. Importantly, pharmacological inhibition of METTL3 exhibited synergy with Notch blockade, significantly enhancing anti-tumor efficacy in preclinical models.

Conclusions: Our findings establish the METTL3/JAG2 axis as a critical regulator of ESCC progression through IGF2BP2-dependent m6A modification and Notch signaling activation. The demonstrated synergy between METTL3 inhibition and Notch pathway blockade provides a novel therapeutic strategy for ESCC treatment, addressing the unmet need for effective stemness-targeting therapies.

Keywords
Esophageal squamous cell carcinoma; METTL3; Notch inhibitors; Stemness; m6A.
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