Cationic Amphiphilic Polypeptides With Immunogenic Cell Death Inducing Activity for Inhibition of Metastatic Bone Cancer.

Immunogenic cell death (ICD)-mediated activation of antitumor immunity is being explored as a therapeutic approach for cancers with bone metastasis. In this study, several cationic amphiphilic polypeptides were obtained to investigate their architecture-dependent cytotoxicity and ICD-inducing properties. Among these candidates, the random copolymer PRP was identified as the most effective lead polymer, exhibiting superior tumor cell-killing activity and selectivity compared with the corresponding block copolymer and homopolymer analogues. Mechanistic investigations showed that PRP disrupted tumor cell membranes and induced necrotic cell death. In addition, PRP triggered a pronounced ICD response by impairing mitochondrial function and increasing intracellular reactive oxygen species levels. In multiple murine models, PRP effectively suppressed tumor progression, metastasis, and recurrence through direct oncolysis and activation of antitumor immune responses, while markedly reducing tumor-associated bone damage. These findings demonstrate that PRP functions as a potent ICD-inducing polypeptide with considerable potential for the immunotherapy of metastatic bone tumors.