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N⁶-methyladenosine (m⁶A) is the most common and abundant endogenous mRNA methylation in eukaryotic cells (Huang et al., 2020; Wang et al., 2014). The regulation of this modification is achieved through the coordinated action of three distinct protein groups. The “writers” (methyltransferase complex), which include METTL3, METTL14, and WTAP, are responsible for adding the m⁶A modification. In contrast, the “erasers” (demethylases), which consist of FTO and ALKBH5, remove this chemical mark. Lastly, the “readers,” a group of proteins including YTHDF1/2/3 and YTHDC1/2, recognize and bind to m⁶A-modified RNA, thereby modulating diverse RNA metabolic processes. The m⁶A reader proteins YTHDFs exhibit distinct canonical functional roles: YTHDF1 primarily boosts the efficiency of mRNA translation, YTHDF2 enhances mRNA degradation, and YTHDF3 exerts dual functions by supporting both translation and degradation of mRNA, with its role varying depending on the specific biological context (Roundtree et al., 2017; Shi et al., 2017; Wang et al., 2014; Wang et al., 2015; Zaccara et al., 2019). Recent studies have revealed that YTHDF proteins can influence the efficacy of RT through mechanisms, such as modulating DNA repair and shaping the tumor immune microenvironment (TIME) (Du et al., 2023; Shao et al., 2023; Shi et al., 2023; Wang et al., 2023a; Wang et al., 2023c; Wen et al., 2024a; Yin et al., 2023). Elucidating the functions and mechanisms of YTHDF proteins within the context of radiation biology holds significant potential for advancing therapeutic strategies in cancer RT.

This review provides an overview of recent progress in elucidating the mechanisms by which YTHDF proteins in tumor and immune cells modulate the therapeutic efficacy of RT. By synthesizing current knowledge on the functions of YTHDF proteins in the context of IR, we emphasize their indispensable role in shaping RT outcomes.