Engineering the Host Defense Peptide from Scorpion Venom for Safer and More Potent Antibreast Cancer Activity.

Host Defense Peptides (HDPs) are key components of the innate immune system and promising candidates for anticancer therapy due to their ability to interact with cell membranes. In this study, we investigated the structure-activity relationship of the scorpion venom-derived HDP IsCT1 and its rationally designed analogs against breast cancer models. The analog AKFK-IsCT1 emerged as the lead compound, exhibiting potent antitumor activity while reducing cytotoxicity toward nontumorigenic cells. Notably, AKFK-IsCT1 maintained an optimal balance of positive charge and helical conformation, which proved more critical for anticancer efficacy than charge alone. When combined with photodynamic therapy using hypericin, AKFK-IsCT1 displayed remarkable synergistic effects, enabling substantial dose reduction of both agents. In a triple-negative breast cancer mouse model, AKFK-IsCT1 treatment reduced tumor burden and elicited immune-associated responses, supporting its potential as a selective and multifunctional therapeutic strategy against aggressive breast cancers.