Abstract
Diffuse large B-cell lymphoma (DLBCL) is one of the most prevalent lymphomas, and can be classified as activated B-cell DLBCL (ABC-DLBCL) or germinal center B-cell DLBCL (GCB-DLBCL) according to molecular subtypes. Studies have shown that drug resistance is an important factor in its therapeutic failure. Tumor-specific drug delivery nanocarriers may be a promising strategy for the treatment of lymphoma. Herein, we developed a nanomedicine (RTX-DOX/DMF-Lip, RDDL) carrying the chemotherapeutic drugs doxorubicin (DOX) and dimethyl fumarate (DMF), and surface-modified with rituximab (RTX), which can recognize CD20 antigen when it comes into contact with the surface of a B-lymphoma cell. In the study, we found that DOX and DMF can be delivered to the tumor site precisely and demonstrate a potent synergistic anti-tumor effect. Once the nanomedicine was internalized, it induced apoptosis through ROS generation and the activation of caspase-3. Concurrently, DMF directly reduced the levels of glutathione (GSH) in tumor cells by inhibiting System Xc(-), thereby resulting in impaired ROS detoxification and fostering an environment conducive to lipid peroxidation (LPO) and ferroptosis. Furthermore, the ROS generated by DOX synergistically propelled the process of ferroptosis, creating a potent therapeutic effect. These effects were validated in the GCB-DLBCL mouse model, where RDDL had a more potent killing effect compared to free drugs by striking SU-DHL-10 cells through a dual mechanism of apoptosis and ferroptosis, providing a new therapeutic strategy for the treatment of drug-resistant GCB-DLBCL.