Synergizing Ferroptosis and Immunotherapy via a PROTAC/PDT/HPK1 Inhibitor‐Loaded Nanoplatform for Enhanced Antitumor Efficacy

Abstract Current cancer therapies face challenges including limited efficacy against “undruggable” targets (e.g., SLC7A11, a ferroptosis resistance regulator), insufficient synergy between ferroptosis and immunity, and systemic toxicity from proteolysis‐targeting chimeras (PROTACs). To address these, a triple‐action nanoplatform is engineered integrating PROTAC‐SLC7A11, a disulfide‐linked prodrug (PPA‐SS‐AA), and HPK1 inhibitor ZYF0033. PROTAC‐SLC7A11 degrades SLC7A11, disrupting cystine uptake and glutathione (GSH) synthesis. Light‐activated pyropheophorbide α (PPA) generates cytotoxic reactive oxygen species (ROS), while redox‐responsive cleavage of PPA‐SS‐AA depletes intracellular GSH, amplifying redox imbalance and lipid peroxidation to induce ferroptosis. Concurrently, photodynamic therapy (PDT) triggers immunogenic cell death (ICD), releasing damage‐associated molecular patterns that prime dendritic cells and enhance T‐cell infiltration. ZYF0033 blocks immunosuppressive HPK1 signaling, potentiating T‐cell activation. In vitro and in vivo evaluations demonstrate efficient SLC7A11 degradation, GSH depletion, and robust ferroptosis via lipid peroxide accumulation. This platform also enhances ICD‐immune axis activation through combined PDT and HPK1 inhibition. By integrating metabolic targeting (SLC7A11), redox dysregulation, and immune checkpoint modulation, this combinatorial approach overcomes monotherapy limitations, offering a novel strategy for synergistic ferroptosis‐immunotherapy against malignancies.