Cationic Spherical Polypeptides with Immunogenic Cell Death Inducing Activity for Oncolytic Immunotherapy

Immunogenic cell death (ICD) has gained increasing attention due to its capacity to trigger anticancer immunity. Herein, we report a series of fabricated cationic spherical polypeptides (CSPs) designated CSP-0 to CSP-57, with oncolytic activity and ICD-inducing ability. CSP-57 exerted the optimal broad-spectrum and tumor-cell-selective cytotoxicity by disrupting cell membranes and inducing cell necrosis. Moreover, CSP-57 damaged mitochondrial membranes, thereby elevating intracellular levels of reactive oxygen species, leading to robust ICD of tumor cells featured by multiple damage-associated molecular patterns, including calreticulin, high-mobility group box 1, and adenosine triphosphate. In vivo anticancer activity determination results suggested that CSP-57 significantly delayed B16F10 tumor growth in mice by direct oncolysis and subsequent induction of ICD. The immunotherapeutic efficacy of CSP-57 was characterized by elevated ratios of cytotoxic T cells in tumors and spleens. Briefly, this work indicates that CSPs represent a promising strategy for oncolytic immunotherapy.