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

Abstract

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.

Construction and in vitro evaluation of pH-sensitive nanoparticles to reverse drug resistance of breast cancer stem cells

“…The pH of the lysosomes of tumor cells is 5.5, and experimental results show that the drug is rapidly released at this acidity. PBAE is a pH-sensitive polymer, which can undergo strong protonation under acidic lysosomal conditions [ 26 ]. At the same time, the protonation causes abundant chloride ions and water molecules to flow into the lysosome, resulting in osmotic pressure increasing and e lysosome rupturing [ 27 ].…”

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer

“…Following glycolysis inhibition, the HK2-degraders induce mitochondrial damage and pyroptosis, eventually leading to immunogenic cell death. This last effect reactivates the antitumor immune response, demonstrating how HK2 inhibition may also reverse an immunosuppressive TME [88].…”

“…More recently, the technology of proteolysis-targeting chimera has been applied to discover new compounds that are capable of degrading HK2, the rate-limiting enzyme of glycolysis [88]. Following glycolysis inhibition, the HK2-degraders induce mitochondrial damage and pyroptosis, eventually leading to immunogenic cell death.…”

Thermal Proteome Profiling Strategy Identifies CNPY3 as a Cellular Target of Gambogic Acid for Inducing Prostate Cancer Pyroptosis

“…Pyroptosis is a type of programmed cell death characterized by cell rupture and proinflammatory factors release. − It has been proven that pyroptosis, possessing strong immunogenic properties, can effectively activate immune responses and initiate tumor immunotherapy. Extensive investigation into the underlying mechanisms of tumor pyroptosis has yielded novel insights and identified molecular targets that hold promise for advancing cancer immunotherapy. − The clinical value of pyroptosis has been demonstrated in the prevention and treatment of liver cancer and gastric cancer, through its involvement in invasion, multiplication, and migration, affecting cancer prognosis. − Moreover, current evidence suggests that pyroptosis plays a role in the development of prostate cancer and can be used for early diagnosis and treatment of drug-resistant patients. , …”