Background <p>Photon radiation has been shown to stimulate the secretion of radioresistant factors from tumor cells, ultimately promoting tumor angiogenesis and metastasis. On the other hand, heavy-ion radiotherapy has been demonstrated to control tumor angiogenesis and metastasis levels. The molecular mechanisms responsible for the different angiogenic responses to photon and heavy-ion irradiation are not fully understood. This study aims to explore the irradiation-responsive genes related to tumor angiogenesis and reveal the regulatory effect.</p> Methods <p>In order to clarify the potential regulatory mechanisms of tumor angiogenesis after X-ray or carbon ion (C-ion) irradiation, we performed RNA-sequencing (RNA-seq), as well as bioinformatics, public database analysis, Western blotting, immunohistochemistry, and immunofluorescence.</p> Results <p>In this study, we identified the long intergenic noncoding RNA PRDM10 divergent transcript (PRDM10-DT), which was responsive to X-rays but not carbon ions. Mechanistically, PRDM10-DT triggers tumor angiogenesis by upregulating the TGF-β1/VEGF signaling pathway through its competitive binding to miR-663a. Additionally, the transcription factor SP1 facilitated the transcription of PRDM10-DT by binding to its promoter region. It’s notable that the DNA-binding activity of SP1 was enhanced by reactive oxygen species (ROS). The knockdown of either PRDM10-DT or SP1 effectively inhibited NSCLC angiogenesis and metastasis.</p> Conclusion <p>These results illustrate the proangiogenic function of the PRDM10-DT/miR-663a/TGF-β1 axis and reveal the regulatory role of ROS and SP1 in the upstream response to radiation, with differential ROS production mediating the differential angiogenesis levels after X-ray and C-ion irradiation. Our findings suggest the potential of PRDM10-DT as a nucleic acid biomarker after radiotherapy and that targeting this gene could be a therapeutic strategy to counteract angiogenesis in NSCLC radiotherapy.</p>