pH-responsive polymeric-peptide complex enhances tumor immunogenic cell death by membrane disruption

Melittin, the principal bioactive component of bee venom, exhibits potent anticancer activity. However, its clinical application is hindered by nonspecific hemolytic toxicity. In this study, we developed a pH-responsive polymeric-peptide complex (PCM) to improve anti-tumor activity of melittin while minimizing off-target effects. PCM remained structurally stable under physiological conditions (pH 7.4) but underwent rapid disassembly in the mildly acidic tumor microenvironment (pH 6.8) to expose melittin. The exposed melittin bound to tumor cell membranes, compromised membrane integrity through transmembrane pore formation, leading to tumor cell death. This membrane disruption elicited the release of damage-associated molecular patterns, thereby activating antitumor immune responses. In a murine breast cancer model, low dose administration of PCM significantly inhibited tumor recurrence and metastasis, and generated durable antitumor immunological memory without significant side effects. The mechanistic actions and morphological effects of PCM on tumor cells were thoroughly investigated, providing important theoretical insights for the clinical translation of anticancer peptides.