Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy PMID: 37751743

GLP-1 and Obesity Research

2026-08-18

Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy

Cell Chem Biol. 2023 Sep 21:S2451-9456(23)00291-X. doi: 10.1016/j.chembiol.2023.09.001.

Haisheng Yu ¹ , Jing Liu ² , Xia Bu ³ , Zhiqiang Ma ⁴ , Yingmeng Yao ¹ , Jinfeng Li ⁵ , Tiantian Zhang ⁶ , Wenjing Song ⁷ , Xiangling Xiao ¹ , Yishuang Sun ¹ , Wenjun Xiong ¹ , Jie Shi ¹ , Panpan Dai ⁸ , Bolin Xiang ¹ , Hongtao Duan ⁹ , Xiaolong Yan ⁹ , Fei Wu ¹⁰ , Wen Cai Zhang ¹¹ , Dandan Lin ¹² , Hankun Hu ¹³ , Haojian Zhang ⁶ , Frank J Slack ¹⁴ , Housheng Hansen He ¹⁵ , Gordon J Freeman ¹⁶ , Wenyi Wei ¹⁷ , Jinfang Zhang ¹⁸

Affiliations

1. Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
2. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
4. Department of Medical Oncology, Senior Department of Oncology, Chinese PLA General Hospital, The Fifth Medical Center, 28 Fuxing Road, Beijing 100853, China.
5. Institute of Oncology, Chinese PLA General Hospital, The Fifth Medical Center, 28 Fuxing Road, Beijing 100853, China.
6. Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan 430071, China.
7. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
8. Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
9. Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.
10. Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, P.R.China.
11. Department of Cancer Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida. Orlando, FL 32827, USA.
12. Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430061, China.
13. Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
14. Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
15. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
16. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
17. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
18. Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].

Abstract

The tumor microenvironment (TME) is a heterogeneous ecosystem containing Cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N⁶-methyladenosine (m⁶A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung Cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m⁶A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

Keywords

METTL3; PD-L1; cancer immunotherapy; chemokines; tumor microenvironment.