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.

免疫原性细胞死亡（ICD）因其触发抗癌免疫的能力而受到越来越多的关注。在此，我们报道了一系列人工制造的阳离子球形多肽（CSP），命名为CSP-0至CSP-57，具有溶瘤活性和ICD诱导能力。 CSP-57 通过破坏细胞膜并诱导细胞坏死，发挥最佳的广谱和肿瘤细胞选择性细胞毒性。此外，CSP-57 损伤线粒体膜，从而提高细胞内活性氧水平，导致肿瘤细胞产生强大的 ICD，其特征是多种损伤相关分子模式，包括钙网蛋白、高迁移率族盒 1 和三磷酸腺苷。体内抗癌活性测定结果表明，CSP-57 通过直接溶瘤和随后的 ICD 诱导，显着延缓了小鼠 B16F10 肿瘤的生长。 CSP-57 的免疫治疗功效的特点是肿瘤和脾脏中细胞毒性 T 细胞的比例升高。简而言之，这项工作表明 CSP 代表了一种有前途的溶瘤免疫治疗策略。