The ubiquitin-proteasome system (UPS) with a capacity of degrading multiple intracellular proteins is an essential regulator in tumor immunosurveillance. Tumor cells that escape from recognition and destruction of immune system have been consistently characterized an important hallmark in the setting of tumor progression. Little know about the exact functions of UPS-related genes (UPSGs) and their relationships with antitumor immunity in head and neck squamous cell carcinoma (HNSCC) patients. In this study, for the first time, we comprehensively identified 114 differentially expressed UPSGs (DEUPSGs) and constructed a prognostic risk model based on the eight DEUPSGs (BRCA1, OSTM1, PCGF2, PSMD2, SOCS1, UCHL1, UHRF1, and USP54) in the TCGA-HNSCC database. This risk model was validated using multiple data sets (all P < 0.05). The high-risk score was found to be an independently prognostic factor in HNSCC patients and was significantly correlated with T cells suppression. Accordingly, our risk model can act as a prognostic signature and provide a novel concept for improving the precise immunotherapy for patients with HNSCC.

Background Programmed death-1 (PD-1) checkpoint blockade has revolutionized cancer therapy, yet its clinical success is confined to a subset of patients, underscoring the urgent need to understand the molecular underpinnings of programmed cell death ligand 1 (PD-L1) expression to combat immunotherapy resistance. Methods Employing CRISPR/Cas9 screening, we identified key regulators of PD-L1 in non-small cell lung cancer (NSCLC) cells, focusing on the transcription factor CEBPB and its isoform liver-enriched inhibitory protein (LIP). Through chromatin immunoprecipitation (ChIP) and luciferase reporter assays, we explored the interaction between LIP and basic-helix-loop-helix E22 (BHLHE22) in controlling PD-L1 transcription. We also used immunofluorescence and NBD-CI assays to examine how N-terminal acetylation affects LIP’s subcellular localization. The impact of LIP on tumor growth was assessed via subcutaneous tumorigenicity assays, while immunohistochemistry and immunofluorescence were used to analyze LIP-induced alterations in the tumor immune microenvironment. Results Our research indicates that CEBPB, particularly its LIP isoform, significantly suppresses PD-L1 expression in NSCLC cells. This suppression is contingent on LIP’s N-terminal acetylation by the N-terminal acetyltransferase A complex, which facilitates LIP’s nuclear entry and interaction with BHLHE22. This interaction leads to the formation of a co-repressor complex at the PD-L1 promoter, effectively reducing PD-L1 expression and enhancing the tumor immune response. Conclusions Identifying CEBPB, especially the LIP isoform, as a pivotal regulator of PD-L1 expression sheds light on the mechanisms behind PD-1 blockade resistance in NSCLC. Our findings suggest that modulating LIP’s function or its molecular interactions might offer a novel approach to boosting the efficacy of immunotherapies.