YTHDF2: a key RNA reader and antitumor target

Sai Xiao; Songqi Duan; Michael A Caligiuri; Shoubao Ma; Jianhua Yu

doi:10.1016/j.it.2025.04.003

YTHDF2: a key RNA reader and antitumor target

Trends Immunol. 2025 Jun;46(6):485-498. doi: 10.1016/j.it.2025.04.003. Epub 2025 May 20.

Authors

Sai Xiao¹, Songqi Duan¹, Michael A Caligiuri², Shoubao Ma³, Jianhua Yu⁴

Affiliations

¹ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
² Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA. Electronic address: mcaligiuri@coh.org.
³ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA. Electronic address: shma@coh.org.
⁴ Division of Hematology and Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA; Institute for Precision Cancer Therapeutics and Immuno-Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA; The Clemons Family Center for Transformative Cancer Research, University of California, Irvine, CA 92697, USA. Electronic address: jianhuay@uci.edu.

PMID: 40399203
DOI: 10.1016/j.it.2025.04.003

Abstract

N⁶-methyladenosine (m⁶A) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major m⁶A 'reader', was initially recognized for promoting mRNA decay but is now also known to enhance translation by binding to methylated mRNAs. YTHDF2 maintains the function of immune suppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while also supporting cytotoxic immune cells, including natural killer (NK) and CD8⁺ T cells. Additionally, YTHDF2 acts as a tumor-intrinsic regulator orchestrating tumor immune evasion. Its multifaceted roles in tumor immunity make YTHDF2 a promising yet challenging therapeutic target. This review explores the complex roles and mechanisms of YTHDF2 in cancers, immune regulation, and tumor immune evasion and highlights emerging therapeutic strategies that target YTHDF2.

Keywords: RNA metabolism; YTHDF2; immunotherapy; m(5)C; m(6)A; tumor immunology; tumor microenvironment.

Publication types

Review

MeSH terms

Adenosine / analogs & derivatives
Adenosine / metabolism
Animals
Humans
Neoplasms* / genetics
Neoplasms* / immunology
Neoplasms* / therapy
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / immunology
RNA-Binding Proteins* / metabolism
Tumor Escape
Tumor Microenvironment

Substances

RNA-Binding Proteins
YTHDF2 protein, human
Adenosine
N-methyladenosine
RNA, Messenger