HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression

Yi Zhang, Mingjie Wang, Ling Ye, Shengqi Shen, Yuxi Zhang, Xiaoyu Qian, Tong Zhang, Mengqiu Yuan, Zijian Ye, Jin Cai, Xiang Meng, Shiqiao Qiu, Shengzhi Liu, Rui Liu, Weidong Jia, Xianzhu Yang (), Huafeng Zhang (), Xiuying Zhong () and Ping Gao ()
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Yi Zhang: South China University of Technology
Mingjie Wang: South China University of Technology
Ling Ye: University of Science and Technology of China
Shengqi Shen: Southern Medical University
Yuxi Zhang: South China University of Technology
Xiaoyu Qian: South China University of Technology
Tong Zhang: Southern Medical University
Mengqiu Yuan: University of Science and Technology of China
Zijian Ye: South China University of Technology
Jin Cai: South China University of Technology
Xiang Meng: South China University of Technology
Shiqiao Qiu: South China University of Technology
Shengzhi Liu: South China University of Technology
Rui Liu: University of Science and Technology of China
Weidong Jia: University of Science and Technology of China
Xianzhu Yang: South China University of Technology, Guangzhou International Campus
Huafeng Zhang: University of Science and Technology of China
Xiuying Zhong: Southern Medical University
Ping Gao: South China University of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Immune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune checkpoint inhibitor therapy because of immune evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate immune cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes tumor immune evasion in a CD8+ T cell-dependent manner by activating STAT1/PD-L1 in tumor cells. Mechanistically, HKDC1 binds to and presents cytosolic STAT1 to IFNGR1 on the plasma membrane following IFNγ-stimulation by associating with cytoskeleton protein ACTA2, resulting in STAT1 phosphorylation and nuclear translocation. HKDC1 inhibition in combination with anti-PD-1/PD-L1 enhances in vivo T cell antitumor response in liver cancer models in male mice. Clinical sample analysis indicates a correlation among HKDC1 expression, STAT1 phosphorylation, and survival in patients with hepatocellular carcinoma treated with atezolizumab (anti-PD-L1). These findings reveal a role for HKDC1 in regulating immune evasion by coupling cytoskeleton with STAT1 activation, providing a potential combination strategy to enhance antitumor immune responses.

Date: 2024
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DOI: 10.1038/s41467-024-45712-2

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