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In this study, we found that the E2\/E3 hybrid ubiquitin enzyme UBE2O interacted with CDKL1, facilitating its ubiquitination and subsequent degradation at the K21 residue and thereby negatively regulating the stability of the CDKL1 protein in lung cancer. Silencing UBE2O stabilized CDKL1 to inhibit YBX1\u2010mediated PD\u2010L1 transcription, which consequently promoted the infiltration and activation of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, thereby enhancing the antitumor immune response in lung cancer. Furthermore, targeting UBE2O in combination with radiotherapy and anti\u2010PD\u2010L1 immunotherapy resulted in stronger antitumor efficacy in lung cancer models. Notably, the UBE2O crosslinking inhibitor arsenic trioxide (ATO) reduced PD\u2010L1 expression and enhanced the efficacy of radioimmunotherapy in preclinical lung cancer models while exhibiting acceptable short\u2010term tolerability. Our findings indicate that targeting the UBE2O\/CDKL1 axis may represent a highly promising strategy for increasing lung cancer sensitization to radioimmunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.76223","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T10:34:16Z","timestamp":1782124456000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["UBE2O Drives Immune Evasion and Radioimmunotherapy Resistance in Lung Cancer by Degrading CDKL1 to Induce PD\u2010L1 Transcription"],"prefix":"10.1002","volume":"13","author":[{"given":"Huichan","family":"Xue","sequence":"first","affiliation":[{"name":"Cancer Center, Hubei Key Laboratory of Precision Radiation Oncology, Institute of Radiation Oncology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Key Laboratory of Biological Targeted Therapy (Huazhong 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