RNA m5C dependent chromatin remodeling enhances radiotherapy response and metastasis control via myeloid reprogramming
Radiation-induced immunosuppressive myeloid cells contribute to therapeutic resistance and metastasis. We identify an IR-responsive TP53-TET2 axis that sustains systemic immunosuppression by reducing m5C in chromatin-associated RNAs (caRNAs), leading to 5-methylcytosine (m5C)-dependent chromatin compaction and suppression of interferon signaling. In contrast, under radiation, Tet2 cKO preserves m5C-marked caRNAs, promoting MBD6-PR-DUB recruitment, removal of repressive H2AK119ub marks, and restoration of chromatin accessibility. This epigenetic remodeling enhances CD8+ T cell cytotoxicity. Pharmacological TET2 inhibition mimics genetic deletion, synergizing with radiotherapy and anti-PD-L1 to suppress tumor growth and metastasis in preclinical models. These findings identify caRNA m5C as a critical regulator of chromatin topology and innate immune plasticity, and establish TET2 as a druggable target to improve the efficacy of radiotherapy and radio-immunotherapy.