METTL family proteins: functional heterogeneity, tumor regulatory networks, immune microenvironment remodeling and therapeutic potential
5 affiliations
- 1Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University
- 2School of Basic Medical Sciences, Southwest Medical University
- 3The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University
- 4Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital)
- 5National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University
Abstract
RNA methylation serves as an essential post-transcriptional epigenetic modification for gene expression regulation. The methyltransferase-like (METTL) family is characterized by conserved methyltransferase domains. These members can recognize multiple RNA substrates including messenger RNA (mRNA), ribosomal RNA (rRNA), and mitochondrial RNA (mtRNA), and engage in a variety of RNA methylation processes. They exhibit markedly heterogeneous tumor-regulatory functions. The METTL3/14 complex regulates tumor proliferation, metastasis, metabolic reprogramming and immunotherapy resistance by catalyzing mRNA N6-methyladenosine (m6A) modification. METTL5 targets rRNA and drives translational reprogramming to participate in tumor progression and T cell immune resistance. METTL17 mediates multiple methylations of mtRNA to deregulate mitochondrial metabolism and drive malignant tumor phenotypes. METTL16 possesses both mRNA m6A catalytic and small nuclear RNA non-catalytic functions, and participates in tumor progression and immune escape. METTL4 catalyzes N6, 2’-O-dimethyladenosine methylation to modulate target gene translation and facilitate tumorigenesis. Beyond RNA methylation, METTL7A/B promotes resistance to tumor-targeted drugs via m6A-independent mechanisms of DNA binding and protein interactions. Notably, the same METTL protein yields distinct immunoregulatory effects in tumor cells, T cells, macrophages and natural killer cells, with obvious context-dependence. In this paper, we systematically summarize structural features and functions of METTL family proteins, together with mechanisms underlying their regulation of the tumor immune microenvironment. We also consolidate the research progress and transformation bottlenecks of multiple targeted candidate molecules. It provides a theoretical basis and new ideas for further investigations of METTL-based tumor immunotargeted therapy.
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BibTeX
@article{ding2026mettl,
title = {{METTL family proteins: functional heterogeneity, tumor regulatory networks, immune microenvironment remodeling and therapeutic potential}},
author = {Qiujie Ding and Peng Wang and Hailong Yu and Zixue Xuan and Chao Yang and Kai Wang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1952952},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1952952/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - METTL family proteins: functional heterogeneity, tumor regulatory networks, immune microenvironment remodeling and therapeutic potential
AU - Qiujie Ding
AU - Peng Wang
AU - Hailong Yu
AU - Zixue Xuan
AU - Chao Yang
AU - Kai Wang
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1952952
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1952952/full
AB - RNA methylation serves as an essential post-transcriptional epigenetic modification for gene expression regulation. The methyltransferase-like (METTL) family is characterized by conserved methyltransferase domains. These members can recognize multiple RNA substrates including messenger RNA (mRNA), ribosomal RNA (rRNA), and mitochondrial RNA (mtRNA), and engage in a variety of RNA methylation processes. They exhibit markedly heterogeneous tumor-regulatory functions. The METTL3/14 complex regulates tumor proliferation, metastasis, metabolic reprogramming and immunotherapy resistance by catalyzing mRNA N6-methyladenosine (m6A) modification. METTL5 targets rRNA and drives translational reprogramming to participate in tumor progression and T cell immune resistance. METTL17 mediates multiple methylations of mtRNA to deregulate mitochondrial metabolism and drive malignant tumor phenotypes. METTL16 possesses both mRNA m6A catalytic and small nuclear RNA non-catalytic functions, and participates in tumor progression and immune escape. METTL4 catalyzes N6, 2’-O-dimethyladenosine methylation to modulate target gene translation and facilitate tumorigenesis. Beyond RNA methylation, METTL7A/B promotes resistance to tumor-targeted drugs via m6A-independent mechanisms of DNA binding and protein interactions. Notably, the same METTL protein yields distinct immunoregulatory effects in tumor cells, T cells, macrophages and natural killer cells, with obvious context-dependence. In this paper, we systematically summarize structural features and functions of METTL family proteins, together with mechanisms underlying their regulation of the tumor immune microenvironment. We also consolidate the research progress and transformation bottlenecks of multiple targeted candidate molecules. It provides a theoretical basis and new ideas for further investigations of METTL-based tumor immunotargeted therapy.
SN - 1664-3224
ER -