UBE2O Drives Immune Evasion and Radioimmunotherapy Resistance in Lung Cancer by Degrading CDKL1 to Induce PD-L1 Transcription.

Resistance to radioimmunotherapy is one of the primary causes of treatment failure in lung cancer patients; however, the underlying mechanisms remain inadequately understood. 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-mediated PD-L1 transcription, which consequently promoted the infiltration and activation of CD8+ T cells, thereby enhancing the antitumor immune response in lung cancer. Furthermore, targeting UBE2O in combination with radiotherapy and anti-PD-L1 immunotherapy resulted in stronger antitumor efficacy in lung cancer models. Notably, the UBE2O crosslinking inhibitor arsenic trioxide (ATO) reduced PD-L1 expression and enhanced the efficacy of radioimmunotherapy in preclinical lung cancer models while exhibiting acceptable short-term tolerability. Our findings indicate that targeting the UBE2O/CDKL1 axis may represent a highly promising strategy for increasing lung cancer sensitization to radioimmunotherapy.