Myeloid reprogramming generates myeloid-derived activating cells to potentiate radiotherapy and suppress metastasis.

Abstract

Radiation induces immunosuppressive myeloid cells that drive therapeutic resistance and metastasis. We identify TET2 as a radiation-induced regulator of myeloid-derived suppressor cells whose expression correlates with poor outcomes in advanced lung cancer patients receiving radio-immunotherapy. Following radiotherapy, myeloid-specific Tet2 deletion suppresses tumor progression and redirects monocyte differentiation toward antigen-presenting myeloid-derived activating cells (MDACs), which augment antitumor T cell responses; spatiotemporal mapping shows that this fate program initiates rapidly in the bone marrow. Mechanistically, a radiation-responsive p53-TET2 axis decreases m5C on chromatin-associated RNAs (caRNAs), enforcing immunosuppressive chromatin compaction and silencing interferon signaling, whereas Tet2 loss restores chromatin accessibility and enhances CD8+ T cell cytotoxicity. Pharmacological TET2 inhibition recapitulates this phenotype and augments radiotherapy and PD-L1 blockade to control primary and metastatic tumors. These findings define MDACs as an immunogenic myeloid subset and establish myeloid reprogramming as a strategy to improve radiotherapy-immunotherapy outcomes.