高分文献速递
客户单位：南方医科大学
期刊：Advanced Functional Materials
影响因子（IF）：19
文章题目：
Synergizing Ferroptosis and Immunotherapy via a PROTAC/PDT/HPK1 Inhibitor-Loaded Nanoplatform for Enhanced Antitumor Efficacy
文章摘要：
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.
原文链接：
https://doi.org/10.1002/adfm.202507906
引用产品及培养细胞：FBS-301 CT26
