Naturally derived oncolytic peptides: from discovery to clinical translation.

Oncolytic peptides have emerged as a distinct class of antitumor agents with the potential to overcome therapeutic resistance and enhance anticancer immunity. Most oncolytic peptides are naturally derived or structurally inspired by natural peptides, and typically display cationic and amphipathic features. Mechanistically, these physicochemical properties enable preferential binding to the negatively charged membranes of cancer cells and subsequent membrane disruption. Beyond direct membrane lysis, many naturally derived oncolytic peptides (NDOPs) perturb intracellular organelle membranes, trigger immunogenic cell death, and modulate immune cells and immune checkpoints, thereby amplifying the cancer-immunity cycle. Through these multifaceted mechanisms, NDOPs show a low tendency to induce drug resistance and can enhance response rates when combined with conventional therapies. Notably, four NDOP-based agents have advanced into clinical trials, underscoring their translational promise. In this review, we summarize the sources, structural features, and mechanisms of NDOPs, highlight innovative therapeutic applications and rational combination strategies, and further discuss the current clinical progress. We also outline key challenges and future directions for the development of NDOPs as next-generation anticancer therapeutics.