Abstract
Cancers co-opt stress response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these pathways also provide protection from ferroptosis, an iron-dependent oxidative cell death pathway triggered by clinically available drugs including chemotherapies, rheumatologic agents, and novel ferroptosis inducers under evaluation in clinical trials. Here, we found that disrupting cap-dependent translation initiation in diffuse large B-cell lymphoma (DLBCL) sensitizes cells to ferroptosis. Specifically, the eIF4A1 inhibitor zotatifin synergized with pharmacologic ferroptosis inducers primarily through suppression of glutathione production, which protects polyunsaturated fatty acids from ferroptotic oxidation. Loss of NRF2 translation, a master regulator of antioxidant genes, was a key consequence of rocaglates, including zotatifin, and other disruptors of cap-dependent initiation. While NRF2 loss alone was insufficient to trigger ferroptosis, it lowered the antioxidant threshold, sensitizing cells to lipid peroxidation and ferroptotic death under additional oxidative stress. In vivo, combining zotatifin with the optimized ferroptosis inducer imidazole ketone erastin significantly reduced tumor burden in DLBCL patient-derived xenografts. Treatment with zotatifin in combination with chimeric antigen receptor (CAR) T cells, a vital treatment modality for DLBCL patients, revealed that zotatifin pre-exposure sensitized DLBCL tumors to CD19-directed CAR T cells in vitro and extended survival of CAR T-cell treated immunocompetent mice bearing syngeneic DLBCL tumors in vivo. Overall, eIF4A1 inhibition-induced translational disruption provides opportunities to leverage the therapeutic impacts of ferroptosis inducers, including cytotoxic immunotherapies.