Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

• DOI: 10.1016/j.cmet.2022.08.002
• Publication Date: 2022-08-24T14:39:39Z
• Authors: Dong Guo; Yingying Tong; Xiaoming Jiang; Ying Meng; Hongfei Jiang; Linyong Du; Qingang Wu; Shan Li; Shudi Luo; Min Li; Liwei Xiao; Haiyan He; Xuxiao He; Qiujing Yu; Jing Fang; Zhimin Lu
• Keywords: Anaerobic glycolysis; Hexokinase

High expression of PD-L1 in tumor cells contributes to tumor immune evasion. However, whether PD-L1 expression in tumor cells is regulated by the availability of nutrients is unknown. Here, we show that in human glioblastoma cells, high glucose promotes hexokinase (HK) 2 dissociation from mitochondria and its subsequent binding and phosphorylation of IκBα at T291. This leads to increased interaction between IκBα and μ-calpain protease and subsequent μ-calpain-mediated IκBα degradation and NF-κB activation-dependent transcriptional upregulation of PD-L1 expression. Expression of IκBα T291A in glioblastoma cells blocked high glucose-induced PD-L1 expression and promoted CD8+ T cell activation and infiltration into the tumor tissue, reducing brain tumor growth. Combined treatment with an HK inhibitor and an anti-PD-1 antibody eliminates tumor immune evasion and remarkably enhances the anti-tumor effect of immune checkpoint blockade. These findings elucidate a novel mechanism underlying the upregulation of PD-L1 expression mediated by aerobic glycolysis and underscore the roles of HK2 as a glucose sensor and a protein kinase in regulation of tumor immune evasion.