Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

Protein synthesis is often dysregulated in cancer, making the selective inhibition of mRNA translation an appealing therapeutic approach. In this study, we demonstrate that targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, produces broad effects on both tumor cells and the tumor immune microenvironment across a variety of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and reduces neutrophil infiltration, thereby enhancing the effectiveness of immune checkpoint blockade. Mechanistic investigations revealed that zotatifin reprograms the tumor’s translational landscape, inhibiting the translation of Sox4 and Fgfr1, while uniformly inducing an interferon (IFN) response across models. The induction of the IFN response is partially attributable to the inhibition of Sox4 translation by zotatifin. A similar upregulation of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Notably, zotatifin exhibits significant synergy with carboplatin, leading to increased DNA damage and an amplified IFN response, resulting in T cell-dependent tumor suppression. These findings highlight a vulnerability in eIF4A within TNBC, identify potential pharmacodynamic biomarkers for zotatifin, and provide a basis for exploring new combination therapies that pair zotatifin with chemotherapy or immunotherapy for the treatment of TNBC.