Inhibition of protein kinase CK2 remodels the tumor immune microenvironment and sensitizes lung cancer to PD-L1 blockade

BACKGROUND: Protein kinase CK2 is a pleiotropic oncogenic serine/threonine kinase implicated in multiple cancer-associated signaling pathways. However, its role in shaping the tumor immune microenvironment (TIME) and regulating immune checkpoint stability remains incompletely understood. METHODS: We integrated analyses of two independent lung cancer patient cohorts with mechanistic and therapeutic studies in lung cancer models. CK2α expression was evaluated in relation to immune infiltration, clinical outcome, and response to immune checkpoint blockade (ICB). The therapeutic impact of combining PD-L1 mAb treatment with three structurally distinct CK2 inhibitors (TBB, CX4945, and SGC-CK2-1) was assessed in vivo. Underlying mechanisms were investigated using transcriptomic profiling, immunophenotyping, and biochemical analyses. RESULTS: Elevated CK2α expression was clinically associated with an immunosuppressive tumor microenvironment (TME), reduced CD8⁺ T cell infiltration, inferior survival, and diminished responsiveness to ICB. In preclinical models, pharmacological CK2 inhibition suppressed tumor growth and reprogrammed the TIME by enhancing T cell infiltration, activation, and proliferation, while alleviating CD8⁺ T cell exhaustion. Importantly, CK2 inhibition sensitized lung tumors to PD-L1 blockade, resulting in robust antitumor efficacy, including complete tumor regression and durable immune protection in a subset of treated mice. Mechanistically, CK2 inhibition reduced PD-L1 protein stability through a defined CK2-TRAF6-PD-L1 axis, in which TRAF6 acts as a critical E3 ubiquitin ligase mediating site-specific ubiquitination of PD-L1 at lysine 281, thereby promoting its proteasomal degradation. CONCLUSIONS: These findings identify CK2 as a key regulator of tumor immune evasion and uncover a previously unrecognized post-translational checkpoint controlling PD-L1 stability via TRAF6-dependent ubiquitination. Targeting CK2 represents a rational strategy to sensitize immunologically "cold" tumors to ICBs and enhance immunotherapeutic efficacy in lung cancer.