Transformable Supramolecular Self‐Assembled Peptides for Cascade Self‐Enhanced Ferroptosis Primed Cancer Immunotherapy

Abstract Immunotherapy has received widespread attention for its effective and long‐term tumor‐eliminating ability. However, for immunogenic “cold” tumors, such as prostate cancer (PCa), the low immunogenicity of the tumor itself is a serious obstacle to efficacy. Here, this work reports a strategy to enhance PCa immunogenicity by triggering cascade self‐enhanced ferroptosis in tumor cells, turning the tumor from “cold” to “hot”. This work develops a transformable self‐assembled peptide TEP‐FFG‐CRApY with alkaline phosphatase (ALP) responsiveness and glutathione peroxidase 4 (GPX4) protein targeting. TEP‐FFG‐CRApY self‐assembles into nanoparticles under aqueous conditions and transforms into nanofibers in response to ALP during endosome/lysosome uptake into tumor cells, promoting lysosomal membrane permeabilization (LMP). On the one hand, the released TEP‐FFG‐CRAY nanofibers target GPX4 and selectively degrade the GPX4 protein under the light irradiation, inducing ferroptosis; on the other hand, the large amount of leaked Fe²⁺ further cascade to amplify the ferroptosis through the Fenton reaction. TEP‐FFG‐CRApY‐induced immunogenic ferroptosis improves tumor cell immunogenicity by promoting the maturation of dendritic cells (DCs) and increasing intratumor T‐cell infiltration. More importantly, recovered T cells further enhance ferroptosis by secreting large amounts of interferon‐gamma (IFN‐γ). This work provides a novel strategy for the molecular design of synergistic molecularly targeted therapy for immunogenic “cold” tumors.