Euphohelioscopin A enhances NK cell antitumor immunity through GSDME-triggered pyroptosis

Abstract Immune evasion by cancer cells poses a significant challenge for natural killer (NK) cell-based immunotherapy. Pyroptosis, a newly discovered form of programmed cell death, has shown great potential for enhancing the antitumor immunity of NK cells. Consequently, targeting pyroptosis has become an attractive strategy for boosting NK cell activity against cancer. In this study, various assays were conducted, including NK cell cytotoxicity assays, flow cytometry, xenograft tumor models, real-time PCR, and ELISA to assess NK cell-mediated cell killing, as well as gene and protein expressions. The results indicated that Euphohelioscopin A (Eupho-A), a potential pyroptosis activator, enhances NK cell-mediated lysis of tumor cells, resulting in inhibiting tumor growth that could be reversed by NK cell depletion. Furthermore, we found that Eupho-A significantly enhanced IFN-γ production in NK cells and synergistically up-regulated GSDME with IFN-γ in cancer cells. Eupho-A also increased the cleavage of GSDME, promoting GZMB-induced pyroptosis, which could be reversed by GSDME knockdown and IFN-γ blockade. Overall, the findings suggested that Eupho-A enhanced NK cell-mediated killing of cancer cells by triggering pyroptosis, making Eupho-A a promising pyroptosis activator with great potential for using in NK cell-based cancer immunotherapy.