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

Abstract

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