Peptide Self‐Assembly for Enhanced Cancer Therapy via Immunogenic Programmed Cell Death: Ferroptosis, Pyroptosis, Necroptosis, and Cuproptosis

ABSTRACT

While immunotherapy has revolutionized cancer treatment, its clinical efficacy is still constrained by tumor heterogeneity, acquired drug resistance, and the immunosuppressive tumor microenvironment. Traditional apoptosis‐driven cancer therapeutic strategies are often inefficient and immunologically silent. In contrast, non‐apoptotic programmed cell death (PCD) pathways (ferroptosis, pyroptosis, necroptosis, and cuproptosis) offer high immunogenicity and the ability to bypass resistance mechanisms, yet their clinical application is limited by poor tumor specificity, off‐target toxicity, and delivery inefficiency. Peptide self‑assembly technology has emerged as a powerful platform to address these challenges, enabling enzyme‑responsive morphological transformation, multivalent target binding, subcellular localization, multifunctional co‑assembly, and artificial enzyme mimicry for precise PCD induction. Despite significant progress, a systematic classification of how peptide assemblies trigger distinct PCD pathways is still lacking. This review categorizes peptide self‑assembly‑induced tumor cell death into five major themes, including ferroptosis, pyroptosis, necroptosis, cuproptosis, and combined death. By summarizing the design principles, key evidence, and anti‑tumor outcomes, this review highlights the unique advantages of peptide self‑assembly. It provides a theoretical foundation for developing peptide‑based precision cancer therapies and aims to guide future research toward clinical translation and personalized treatment.