YTHDF2 as a driver of cancer stemness and therapeutic resistance

N6-methyladenosine (m⁶A) is the most abundant reversible internal modification in eukaryotic RNA and plays a major role in post-transcriptional gene regulation. As one of the earliest identified and most widely studied m⁶A readers, YTHDF2 mainly recognizes m⁶A-modified transcripts and regulates their stability, degradation, translation, and subcellular fate. The classical function of YTHDF2 is to promote m⁶A-dependent RNA decay by recruiting RNA degradation machinery. However, recent studies show that YTHDF2 does not act only as a decay factor. In some contexts, it can stabilize selected transcripts, regulate translation, recognize other RNA modifications such as m⁵C, and participate in stress-related RNA compartmentalization. These findings indicate that YTHDF2 functions as a context-dependent RNA fate regulator. In cancer, YTHDF2 regulates multiple malignant processes, including tumor cell proliferation, cell-cycle progression, migration, invasion, epithelial–mesenchymal transition, cancer stem cell maintenance, therapy resistance, metabolic reprogramming, and ferroptosis. YTHDF2 also plays complex roles in tumor immunity. It can support immunosuppressive cells such as tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, thereby promoting immune escape. At the same time, YTHDF2 can maintain the metabolic fitness and cytotoxic activity of CD8 + T cells and natural killer cells, supporting antitumor immunity. This double-edged role makes YTHDF2 both a promising and challenging therapeutic target. In this review, we summarize the biological functions, upstream regulatory mechanisms, cancer-related roles, immune functions, and therapeutic potential of YTHDF2. We also discuss current challenges, including context dependence, YTH family homology, cell-type-specific effects, delivery barriers, and the need for biomarker-guided patient selection. Future strategies should focus on selective modulation of YTHDF2 in defined tumor and immune contexts rather than broad systemic inhibition.