The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage

Significance Lung cancer is the leading cause of cancer-related deaths in the United States. PD-L1 is often overexpressed on cancer cells, driving immune-independent, cell-intrinsic functions that increase resistance to DNA-damaging therapies such as IR or cisplatin. FBXO22, a known ubiquitin E3 ligase, decreases the level of PD-L1 in NSCLC cells and increases their sensitivity to DNA-damaging therapies. Furthermore, targeting cyclin-dependent kinase 5 (CDK5), which is highly expressed in NSCLC, increases FBXO22 levels, leading to decreased expression of PD-L1. Thus, we identify an innovative strategy for treating NSCLC by targeting CDK5 to enhance the efficacy of immunotherapy alone or in combination with DNA-damaging therapies.