N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, serves as a pivotal epitranscriptomic mark that dynamically regulates RNA metabolism—including stability, splicing, translation, and localization—thereby shaping cellular identity and function. This modification is installed by writer complexes (e.g., METTL3/METTL14), erased by demethylases (FTO, ALKBH5), and interpreted by reader proteins. Among these readers, YTHDF2 has emerged as a central regulator, primarily known for binding m6A-modified transcripts and promoting their decay, but recent evidence reveals a more complex role extending to m5C reading and even translational enhancement. YTHDF2 functions as a key integrator of intrinsic genetic programs and extrinsic environmental cues, critically governing hematopoietic stem cell (HSC) fate, immune cell development and activation, and tumor-immune interactions. This review synthesizes advances in understanding YTHDF2’s molecular mechanisms—spanning RNA-stability-dependent and -independent pathways—and its multifaceted roles in hematopoiesis, immunity, and cancer, highlighting its potential as a therapeutic target in immune-related diseases and malignancies.
YTHDF2’s canonical function involves recognizing m6A marks via its conserved YTH domain and recruiting decay machinery like the CCR4-NOT deadenylase complex to shorten poly(A) tails, leading to mRNA degradation. It can also facilitate endoribonucleolytic cleavage via the HRSP12–RNase P/MRP complex. Beyond m6A, YTHDF2 acts as a reader for 5-methylcytosine (m5C) modification, recruiting PABPC1 to stabilize target mRNAs. Intriguingly, a non-canonical, RNA-stability-independent role has been uncovered in ovarian cancer, where YTHDF2 interacts with DDX1 and eIF3F to enhance the translation of m6A-modified transcripts encoding microtubule-associated proteins like CKAP2. This functional versatility—spanning decay, stabilization, and translation—establishes YTHDF2 as a multifaceted post-transcriptional regulator whose impact is highly context-dependent.
During embryonic hematopoiesis, YTHDF2 is essential for the endothelial-to-hematopoietic transition (EHT). In zebrafish models, YTHDF2-mediated decay of m6A-modified arterial transcripts (e.g., notch1a, rhoca) restrains Notch signaling, allowing hemogenic endothelium to differentiate into hematopoietic stem and progenitor cells (HSPCs); loss of YTHDF2 stabilizes these transcripts, locking cells in an endothelial state and blocking HSPC emergence. In adult hematopoiesis, YTHDF2 maintains HSC homeostasis by degrading mRNAs encoding self-renewal transcription factors (Tal1, Gata2, Runx1) and Wnt signaling targets, thereby limiting excessive HSC expansion under steady-state conditions. Under stress or inflammatory conditions, YTHDF2 protects HSC function by clearing proinflammatory transcripts (Stat1, Il6ra, Gadd45g); its deficiency initially expands HSC numbers but ultimately leads to chronic inflammatory signaling, exhaustion, and impaired self-renewal, particularly evident during aging or serial transplantation. Thus, YTHDF2 plays stage-specific yet conserved roles in balancing HSC self-renewal, differentiation, and inflammatory responses.
YTHDF2 exerts precise, cell-type-specific regulation across the immune landscape. In B cells, it promotes pro-B cell proliferation by degrading Foxo1 and Rag1 mRNAs and directs germinal center fate by repressing plasma cell-associated genes (Irf4, Prdm1) at the pre-germinal center stage. In natural killer (NK) cells, YTHDF2 maintains homeostasis and maturation by regulating Eomes and Tardbp mRNA stability, and it sustains IL-15-driven survival, cytotoxicity, and antitumor function. In macrophages, YTHDF2 often promotes immunosuppressive polarization; it suppresses M1 polarization by inhibiting IFN-γ–STAT1 signaling and drives M2 polarization via p53 mRNA decay and NF-κB/MAPK suppression, which in the tumor microenvironment facilitates pro-tumoral phenotypes and reduces antigen presentation. In myeloid-derived suppressor cells (MDSCs), YTHDF2 enhances immunosuppressive capacity by degrading negative regulators of NF-κB and TGF-β signaling (e.g., Bambi, RXRα). In T cells, YTHDF2 supports CD8+ T cell activation and mitochondrial fitness by degrading mitochondrial-related transcripts (Coa3, Mrpl16) to prevent oxidative stress and exhaustion; however, in regulatory T cells (Tregs), it sustains intratumoral immunosuppression by degrading negative regulators of NF-κB (Nfkbie, Traf3). YTHDF2 also restrains Th9 cell differentiation by degrading Gata3 and Smad3 transcripts, and its deletion enhances Th9-mediated antitumor immunity. This dual nature—potentiating effector functions in some contexts while reinforcing immunosuppression in others—underscores its complex role in immune regulation.
In cancer, YTHDF2 frequently exhibits dysregulated expression and contributes to tumor progression by modulating both tumor-intrinsic pathways and the tumor microenvironment (TME). In hematologic malignancies like acute myeloid leukemia (AML), YTHDF2 is often overexpressed and promotes leukemic stem cell (LSC) maintenance by degrading pro-apoptotic and differentiation-related transcripts, thereby sustaining self-renewal and therapy resistance. In solid tumors, YTHDF2 can drive tumor growth by stabilizing oncogenic mRNAs or enhancing translation of pro-tumorigenic factors. Crucially, YTHDF2 shapes the TME by regulating immune cell infiltration and function; for instance, it promotes the accumulation and suppressive activity of MDSCs and Tregs while impairing NK and CD8+ T cell cytotoxicity in many contexts. This immunomodulatory role positions YTHDF2 as a key node in cancer immune evasion, making it an attractive target for combination therapies that aim to simultaneously disrupt tumor-intrinsic survival pathways and reinvigorate antitumor immunity.
Therapeutic targeting of YTHDF2 holds significant promise but requires careful consideration of its dual roles in normal physiology and disease. Small-molecule inhibitors and degraders of YTHDF2 are under development, showing efficacy in preclinical models of AML and solid tumors by inducing differentiation, apoptosis, and enhancing immune-mediated clearance. However, given YTHDF2’s critical function in HSC maintenance and immune homeostasis, potential on-target toxicities—such as HSC exhaustion or autoimmune-like inflammation—must be managed through strategies like intermittent dosing, targeted delivery to malignant cells, or combination with immunotherapy to exploit synthetic lethality. Future directions include elucidating the context-dependent effects of YTHDF2’s m6A vs. m5C reading activities, developing isoform-specific inhibitors, and integrating YTHDF2 modulation with checkpoint blockade or cellular therapies to overcome therapy resistance and improve cancer treatment outcomes.
Experimental study
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Emerging role of RNA modification reader YTHDF2 in hematopoiesis, immunity, and cancer
14-Mar-2026