Ythdf2, an N6-methyladenosine (m6A) reader, plays a crucial role in regulating mRNA degradation. It binds to m6A-modified mRNAs, leading to their decay, thus influencing gene expression and various biological processes. It is involved in pathways like NF-κB signaling and has significance in tumor-related immunology and cancer progression [1,2,3,4,5,6,7,8,10]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In myeloid cells, loss of Ythdf2 after ionizing radiation (IR) enhances antitumor immunity and overcomes tumor radioresistance by modulating myeloid-derived suppressor cell (MDSC) differentiation, infiltration, and suppressive function. The IR-induced YTHDF2 expression depends on NF-κB signaling, forming an IR-YTHDF2-NF-κB circuit [1]. In tumor-associated macrophages (TAMs), Ythdf2 deficiency reprograms TAMs towards an antitumoral phenotype, enhancing CD8+ T cell-mediated antitumor immunity [2]. In MYC-driven breast cancer, disrupting YTHDF2-dependent mRNA degradation triggers apoptosis [5]. In glioblastoma, YTHDF2 promotes cholesterol dysregulation and invasive growth [6]. In hepatocellular carcinoma, YTHDF2 upregulation is related to sorafenib resistance [7]. In bladder cancer, YTHDF2 promotes cancer progression by suppressing the RIG-I-mediated immune response [8]. In NK cells, Ythdf2 deficiency impairs antitumor and antiviral activity [9]. In prostate cancer, YTHDF2 mediates the mRNA degradation of tumor suppressors LHPP and NKX3-1, regulating AKT phosphorylation-induced tumor progression [10].

In conclusion, Ythdf2 is a key regulator in multiple biological processes, especially in tumor-related immunology and cancer progression. Studies using KO/CKO mouse models have revealed its role in various disease conditions, providing potential therapeutic targets for cancers, such as improving radiotherapy and immunotherapy combinations, and enhancing the efficacy of cancer treatments.