Ythdf2, the YT521-B homology domain 2, is a crucial N6-methyladenosine (m6A) reader protein. It mainly mediates the degradation of m6A-modified mRNAs, thus regulating gene expression at the post-transcriptional level. This function is involved in multiple biological pathways, such as NF-κB signaling, and is of great significance in various biological processes and disease conditions. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its functions.

In myeloid cells, loss of Ythdf2 in murine models augments antitumor immunity and overcomes tumor radioresistance by altering myeloid-derived suppressor cell (MDSC) differentiation and inhibiting MDSC infiltration and suppressive function. Ionizing radiation (IR)-induced YTHDF2 expression relies on NF-κB signaling, and YTHDF2 in turn activates NF-κB by degrading transcripts encoding negative regulators of NF-κB signaling, forming an IR-YTHDF2-NF-κB circuit [1]. In tumor-associated macrophages (TAMs), YTHDF2 deficiency suppresses tumor growth by reprogramming TAMs toward an antitumoral phenotype and enhancing CD8+ T cell-mediated antitumor immunity, with its expression in TAMs regulated by interleukin-10-STAT3 signaling [2]. In MYC-driven triple-negative breast cancer (TNBC) cells, disrupting YTHDF2-dependent mRNA degradation triggers apoptosis, as YTHDF2 interacts with mRNAs encoding proteins in the MAPK pathway, and its depletion leads to endoplasmic reticulum stress-induced apoptosis [3].

In conclusion, Ythdf2 plays a vital role in regulating gene expression through mRNA degradation. Studies using KO/CKO mouse models have revealed its significance in cancer-related processes, such as tumor radioresistance, TAM-mediated antitumor immunity, and cancer cell apoptosis. These findings suggest that Ythdf2 could be a potential therapeutic target in cancer treatment.