Dr. Feng Shao

Pyroptosis is a proinflammatory cell death executed by the gasdermin-family pore-forming proteins. Among the family, gasdermin D (GSDMD) is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain in GSDMD that perforates plasma membrane. Using a bioorthogonal chemical biology approach allowing controlled delivery of active gasdermin into tumors in mice, we found that pyroptosis of < 15% tumour cells could clear the entire 4T1 mammary tumourgraft, which was absent in immune-deficient mice or upon T-cell depletion. Thus, pyroptosis stimulates potent and effective antitumour immunity. In antitumor immunity, cytotoxic lymphocyte relies on granzymes to kill target cells. We found that natural killer cells and cytotoxic T lymphocytes kill GSDMB-positive cells through pyroptosis, mediated by granzyme A (GZMA) cleavage of GSDMB. IFN-γ upregulates GSDMB expression and promotes pyroptosis of cancer cells including that by CAR-T/TCR-T cells. Thus, gasdermin-executed pyroptosis serves as a cytotoxic lymphocyte killing mechanism, playing an important role in cancer immunotherapy. We recently discovered a novel cytosolic innate immune receptor alpha-kinase 1 (ALPK1) that recognizes a bacterial metabolite ADP-heptose. ADP-heptose-activated ALPK1 phosphorylates the TIFA adaptor, thereby stimulating the NF-κB signaling and proinflammatory cytokine production. I will also discuss the function of ALPK1-TIFA axis in cancer immunity.