Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy.

Hexokinase 2 (HK2) is the principal rate-limiting enzyme in the aerobic glycolysis pathway and determines the quantity of glucose entering glycolysis. However, the current HK2 inhibitors have poor activity, so we used proteolysis-targeting chimera (PROTAC) technology to design and synthesize novel HK2 degraders. Among them, C-02 has the best activity to degrade HK2 protein and inhibit breast cancer cells. It is demonstrated that C-02 could block glycolysis, cause mitochondrial damage, and then induce GSDME-dependent pyroptosis. Furthermore, pyroptosis induces cell immunogenic death (ICD) and activates antitumor immunity, thus improving antitumor immunotherapy in vitro and in vivo. These findings show that the degradation of HK2 can effectively inhibit the aerobic metabolism of breast cancer cells, thereby inhibiting their malignant proliferation and reversing the immunosuppressive microenvironment.

CJ2: A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane.

Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ2-reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ2 could arouse the immune system and promote CD8+ T cell infiltration. Meanwhile, CJ2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response.