Ludwig Chicago researchers have previously demonstrated that the m6A RNA-binding protein YTHDF2, which is expressed at high levels in myeloid-derived suppressor cells following radiotherapy (RT), plays a key role in the immunosuppression induced by those cells—and that its inhibition boosts RT efficacy in mouse models. In a November paper in the Journal of Experimental Medicine, a Center team led by Co-director Ralph Weichselbaum, Dapeng Chen, Chuan He and Hua Laura Liang reported that YTHDF2 is also a radiation-induced immune checkpoint in dendritic cells (DCs) and that a spike in its expression in DCs following exposure to ionizing radiation correlates with RT failure in patients. They found that radiation induces the expression of SPI1, which drives YTHDF2 expression in DCs. This promotes the m6A-mediated degradation of Notch pathway regulators, which in turn impairs the ability of DCs to cross-present antigens to CD8+ T cells and stimulate their anti-tumor activity, resulting in immune evasion and metastasis. Targeting YTHDF2 restored DC immunogenicity and enhanced RT-induced tumor control. It also improved the efficacy of DC-based cancer vaccines when combined with RT in animal models, suggesting a strategy to overcome RT resistance and limit metastases.
Radiotherapy induces YTHDF2 in dendritic cells impairing cross-presentation and T cell function
Journal of Experimental Medicine, 2025 November 6