Mechanisms and therapeutic potential of YTHDF readers: Linking epitranscriptomics to cancer

YT521-B homology domain-containing family paralogs (YTHDFs), as RNA epigenetic modification effector proteins, fully or partially participate in N 6 -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), and 5-methylcytosine (m 5 C) modifications, which play critical roles in tumor biology and contribute to obtaining and maintaining cancer hallmarks relying on their characteristic protein structures. Accumulating evidence has underscored the involvement of YTHDFs in manipulating RNA stability, translation, and RNA metabolism, thereby influencing tumor initiation, progression, and anti-tumor treatment efficacy through independent RNA epigenetic modification pathways. This review aims to illustrate the essential regulatory mechanisms and pathological consequences of YTHDFs in tumorigenesis and therapeutic resistance. Additionally, we highlight the potential of targeting YTHDFs for cancer therapy, offering promising avenues for the elimination of tumor cells and the amelioration of tumor treatment efficacy. • YTHDFs orchestrate critical molecular processes in tumor cells, primarily influencing RNA translation and stability through m 6 A, m 1 A, and m 5 C modifications. • YTHDFs participate in the maintenance of malignancy phenotypes in multiple tumors, such as tumor invasion, metastasis, cancer stem cell self-renewal, metabolic reprogramming, etc. • The expression and activity of YTHDFs are manipulated by numerous upstream regulatory mechanisms, involving non-coding RNAs, transcription factors, posttranslational modifications, protein-protein interactions, etc. • YTHDFs are implicated in the resistance to antitumor therapeutics, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Targeting YTHDFs provides a promising approach for anti-tumor therapy.