XRRA1 acts as a molecular brake on radiation-induced DNA damage signaling and immunogenic cell death in tumor cells.

Abstract

Radiotherapy kills cancer cells by inducing DNA damage, but adaptive responses that buffer injury and limit immunogenic signaling remain incompletely understood. Although ionizing radiation can activate cytosolic DNA sensing and immunogenic cell death, the tumor-intrinsic regulators linking these processes to radioresistance are not well defined. Here, we show that XRRA1 is a stress-adaptive determinant of radioresponse identified by integrating discovery proteomics into chronic myeloid leukemia with clinical tissue validation and functional studies across multiple tumor models. In peripheral-blood proteomes, XRRA1 was quantitatively reduced in chronic myeloid leukemia yet associated with a favorable prognosis and with networks enriched for RNA regulation, apoptosis, and DNA-repair biology. In human biopsy specimens, XRRA1 protein abundance was increased in radiation-exposed tissues, and in cultured cells, ionizing radiation induced XRRA1 more strongly and persistently in normal cells than in cancer cells. Silencing XRRA1 had little effect on basal growth but markedly enhanced radiation-induced loss of viability, apoptosis, spheroid disruption, and clonogenic failure, while increasing {gamma}H2AX- and DNA-PK-associated damage signaling and linking XRRA1 to non-homologous end joining factors. XRRA1 depletion also amplified cGAS-STING-TBK1-IRF3 activation, interferon-stimulated gene expression, extracellular ATP release, and cell-surface calreticulin exposure. These findings identify XRRA1 as a molecular brake that limits the conversion of radiation-induced DNA damage into immunogenic stress responses. XRRA1, therefore, represents a candidate biomarker of radioadaptive stress and a potential target for radiosensitization and radiotherapy-immunotherapy combinations.