The natural defense peptide caerin1.1/1.9 sequentially induces caspase 3/GSDME-mediated pyroptosis followed by intrinsic apoptosis of epithelial cancer cells

Caerin 1 belongs to a class of host defense peptides with antitumor properties. Caerin 1.1/1.9 have shown promising effects in enhancing the efficacy of immune checkpoint inhibitors and therapeutic vaccines by modulating the tumor microenvironment, particularly by activating tumor-associated macrophages and repolarizing them from an M2 to M1 phenotype. In this study, we demonstrate that caerin1.1/1.9 can induce pyroptosis in epithelial cancer cells (Hela, A549, Huh-7) within 1-hour of administration in vitro , primarily through the caspase 3/GSDME signaling pathway. Furthermore, overnight treatment with caerin1.1/1.9 resulted in apoptosis of Hela cells similar to our previous observation, mediated by the mitochondria/cytochrome C/Apaf-1 pathway. These findings provide insights into the potential mechanisms underlying the antitumor effects of caerin1.1/1.9 and its ability to enhance the efficacy of immunotherapy.