biostudies-literatureZhao XMinistry of Health and Welfare TaiwanChina Scholarship CouncilCancer Center Supporting GrantNational Science Foundation of ChinaKey Science and Technology Program of Shaanxi ProvinceMinistry of Science and Technology TaiwanChina Medical University HospitalChina Medical UniversityNCI NIH HHSNIH2185-2195https://www.ebi.ac.uk/biostudies/studies/S-EPMC11957750biostudies-literatureUnknown82(11)Targeting immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has transformed cancer treatment, with durable clinical responses across a wide range of tumor types. However, a high percentage of patients fail to respond to anti-PD-1/PD-L1 treatment. A greater understanding of PD-L1 regulation is critical to improving the clinical response rate of PD-1/PD-L1 blockade. Here, we demonstrate that PD-L1 is phosphorylated and stabilized by casein kinase 2 (CK2) in cancer and dendritic cells (DC). Phosphorylation of PD-L1 at Thr285 and Thr290 by CK2 disrupted PD-L1 binding with speckle-type POZ protein, an adaptor protein of the cullin 3 (CUL3) ubiquitin E3 ligase complex, protecting PD-L1 from CUL3-mediated proteasomal degradation. Inhibition of CKCancer researchPhosphorylation and Stabilization of PD-L1 by CK2 Suppresses Dendritic Cell Function.PMC11957750MOHW111-TDU-B-221-114016819038562021KW-60MOST109-2314-B-039-006-MY2821035692021KW-57P30 CA016672DMR-111-009DMR-108-BC-6201706280071R01 CA208213CMU108-YTY-02MOST110-2639-B-039-001-ASPR01CA208213Chan LCQu JYu DYing HZhang SWei YChang WCZhao XJiang ZLi YChu YYHung MCYang RLiu CHsu JMHsu JLfalsePhosphorylation and Stabilization of PD-L1 by CK2 Suppresses Dendritic Cell Function.Targeting immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has transformed cancer treatment, with durable clinical responses across a wide range of tumor types. However, a high percentage of patients fail to respond to anti-PD-1/PD-L1 treatment. A greater understanding of PD-L1 regulation is critical to improving the clinical response rate of PD-1/PD-L1 blockade. Here, we demonstrate that PD-L1 is phosphorylated and stabilized by casein kinase 2 (CK2) in cancer and dendritic cells (DC). Phosphorylation of PD-L1 at Thr285 and Thr290 by CK2 disrupted PD-L1 binding with speckle-type POZ protein, an adaptor protein of the cullin 3 (CUL3) ubiquitin E3 ligase complex, protecting PD-L1 from CUL3-mediated proteasomal degradation. Inhibition of CK2022-01-01T00:00:00Z2022 Jun2026-04-18T03:14:18.418Z2025-07-10T03:08:24.511ZS-EPMC119577503538557410.1158/0008-5472.can-21-230010.1158/0008-5472.CAN-21-2300