Inhibiting glycolysis facilitated checkpoint blockade therapy for triple-negative breast cancer.

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.