Dual-pathway blockade overcomes ferroptosis resistance in pancreatic ductal adenocarcinoma via a CD133-targeted manganese-porphyrin theranostic nanoplatform.

Abstract

Ferroptosis has emerged as a promising strategy for treating refractory malignancies such as pancreatic ductal adenocarcinoma (PDAC), but its efficacy is limited by multilayered resistance, including classical tumor-intrinsic pathways and a recently identified cancer-associated fibroblast (CAF) bypass mediated by the TGFβ1-Cys-GSH axis. Most studies have focused on cancer cell-intrinsic mechanisms, leaving ferroptosis-based therapy for PDAC suboptimal. To address this challenge, we propose a dual-pathway blockade that simultaneously targets both the intrinsic cancer cell pathway and the CAF-mediated exogenous pathway. We developed a multifunctional theranostic nanoplatform (MEC), consisting of a manganese-porphyrin metal-organic framework (MOF) loaded with Erastin and surface-modified with an anti-CD133 monoclonal antibody (CD133 mAb) for targeted delivery. In combination with Repsox, MEC disrupts the cysteine exchange cascade between cancer cells and fibroblasts, thereby depleting intracellular glutathione (GSH), enhancing reactive oxygen species (ROS) generation through TCPP-mediated sonodynamic and Mn-driven Fenton-like reactions, and inducing lipid peroxidation-dependent ferroptosis in PDAC cells. Moreover, MEC offers dual-modality magnetic resonance-fluorescence imaging to noninvasively visualize intratumoral GSH dynamics, enabling treatment optimization and precise therapeutic response assessment. Collectively, this study establishes a comprehensive strategy to overcome ferroptosis resistance in pancreatic cancer and introduces a multifunctional theranostic nanoplatform with potential for effective PDAC management.