RNA modifications in radiotherapy resistance and radiosensitization: epitranscriptomic regulation of tumor response...

Radiotherapy (RT) remains a major treatment for solid tumors, but durable tumor control is frequently limited by adaptive DNA repair, altered cell-death thresholds, cancer stemness, metabolic plasticity, and immune escape. RNA modifications have recently emerged as rapid post-transcriptional regulators that enable tumor, stromal, and immune cells to remodel these programs after irradiation. This Mini Review emphasizes three major themes. First, N⁶-methyladenosine (m⁶A) is the best-characterized RNA modification in RT response, with METTL3/METTL14, FTO, ALKBH5, YTH-domain readers, and IGF2BP proteins regulating DNA repair, apoptosis, ferroptosis, stemness, metabolism, and immune checkpoints in a highly context-dependent manner. Second, non-m⁶A modifications, including 5-methylcytosine (m⁵C), N⁴-acetylcytidine (ac⁴C), 7-methylguanosine (m⁷G), and A-to-I RNA editing, are increasingly linked to homologous recombination, metabolic adaptation, innate immune sensing, and immune evasion, although their RT-specific evidence remains limited and should be viewed as emerging rather than established. Third, therapeutic targeting of RNA-modifying enzymes may improve radiosensitization only when guided by tumor type, cellular context, RT dose and fractionation schedule, predictive biomarkers, and normal-tissue safety. Accordingly, we organize current evidence around RNA-modification machinery, tumor-intrinsic mechanisms of radioresistance, immune microenvironment remodeling, and barriers to clinical translation. We further highlight the need to move beyond single-axis models toward dynamic, spatial, and clinically validated analyses of RNA modification networks during fractionated RT.