Li Chong, Tang Yu, Zhang Ruizhi, Shi Liang, Chen Jianying, Zhang Peng, Zhang Ning, Li Wei
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Gastrointestinal Surgery, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China.
Discov Oncol. 2025 Apr 17;16(1):550. doi: 10.1007/s12672-025-02320-w.
Cancer cells are characterized by their altered energy metabolism. A hallmark of cancer metabolism is aerobic glycolysis, also called the Warburg effect. Hexokinase 2 (HK2), a crucial glycolytic enzyme converting glucose to glucose-6-phosphate, has been identified as a central player in the Warburg effect. Deletion of HK2 decreases cancer cell proliferation in animal models without explicit side effects, suggesting that targeting HK2 is a promising strategy for cancer therapy. In this study, we discovered a correlation between HK2 and the tumor immune response in triple-negative breast cancer. Inhibition of HK2 led to a reduction in G-CSF expression in 4T1 cells and a decrease in the development of myeloid-derived suppressor cells which, in turn, enhanced T cell immunity and prolonged the survival of 4T1 tumor-bearing mice. Furthermore, the HK2 inhibitor 3-BrPA improved the therapeutic efficacy of anti-PD-L1 therapy in 4T1 tumor-bearing mouse models. This study highlights the potential of glycolysis-targeting interventions as a novel treatment strategy, which can be combined with immunotherapy for the treatment of triple-negative breast cancer.
癌细胞的特征在于其能量代谢的改变。癌症代谢的一个标志是有氧糖酵解，也称为瓦伯格效应。己糖激酶2（HK2）是一种将葡萄糖转化为6-磷酸葡萄糖的关键糖酵解酶，已被确定为瓦伯格效应的核心参与者。在动物模型中，HK2的缺失可降低癌细胞增殖且无明显副作用，这表明靶向HK2是一种很有前景的癌症治疗策略。在本研究中，我们发现了三阴性乳腺癌中HK2与肿瘤免疫反应之间的关联。HK2的抑制导致4T1细胞中G-CSF表达降低，骨髓来源的抑制性细胞发育减少，这反过来又增强了T细胞免疫，并延长了荷4T1肿瘤小鼠的生存期。此外，HK2抑制剂3-BrPA提高了抗PD-L1疗法在荷4T1肿瘤小鼠模型中的治疗效果。本研究突出了靶向糖酵解干预作为一种新型治疗策略的潜力，其可与免疫疗法联合用于治疗三阴性乳腺癌。
