TET2 Blockade Reprograms Radiation-Induced MDSCs into Activating Cells in Preclinical Cancer Models

The team first measured TET2 protein and m5C RNA marks in serial blood samples from 33 stage IV non-small cell lung cancer patients receiving high-dose radiation plus nivolumab and ipilimumab. MDSCs showed the highest TET2 expression, which rose further post-radiation in non-responders. Parallel mouse experiments deleted TET2 only in myeloid lineages; these animals exhibited slower primary tumor progression, longer survival, and fewer metastases than wild-type controls after radiation.

Radiation activated p53 within 24 hours in bone marrow, inducing TET2 to erase m5C marks on chromatin-associated RNAs. Loss of these marks compacted chromatin and silenced type I interferon genes. Without TET2, MBD6 recruitment maintained open chromatin, allowing myeloid cells to differentiate into MDACs that presented tumor antigens and supported CD8+ T cell function rather than suppressing it.

Prior observational data linking post-radiation MDSC expansion to shorter survival are mechanistically explained here, yet the study remains limited to genetically engineered mice and a small patient cohort without TET2 inhibitor intervention. Next steps require testing small-molecule or RNA-targeted TET2 inhibitors in larger syngeneic models and early-phase human trials to determine dosing windows that avoid hematologic toxicity while preserving anti-tumor effects.