Abstract PS4-06-01: Targeting eIF4A unleashes type I IFN immunity in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) arises from aberrant control of gene expression at multiple levels. Because mRNA abundance explains less than half of the variance in protein levels, it is essential to consider post-transcriptional mechanisms, particularly translational regulation. Our previous publication (PMID: 37874652) suggested that the translation initiation factor eIF4A is a therapeutic vulnerability in TNBC. Targeting eIF4A with the first-in-class inhibitor zotatifin remodels tumor translatome, suppresses TNBC growth, and synergizes with carboplatin in syngeneic mouse models. Methods and Results: In the current study, we further explored the mechanism of zotatifin efficacy in TNBC mouse models and observed that zotatifin treatment induced a marked increase in IFN-β secretion and robust upregulation of interferon-stimulated genes in vitro and in vivo. Immunofluorescence in tumor cells demonstrated cytosolic dsRNA accumulation following eIF4A inhibition, which activates an MDA5-dependent type I IFN pathway in a tumor cell intrinsic manner. Functional blockade of IFNAR1 partially abrogated the efficacy of the combination treatment in syngeneic mouse models, confirming that type I IFN signaling is required for the therapeutic effect. To determine whether these mechanistic insights translate to human TNBC, we next evaluated efficacy across patient-derived xenograft (PDX) models. Across a panel of 8 TNBC PDX models, the zotatifin-carboplatin combination achieved complete responses in 1 model (1/8), partial responses in 3 models (3/8), and stable disease in 2 models (2/8). Zotatifin-containing arms triggered type I IFN transcriptional programs in both tumor and stromal compartments. Tumors with higher basal IFN-related gene expression exhibited greater treatment sensitivity, suggesting type I IFN activity as a potential predictive biomarker of response. Conclusions: These data define the mechanistic basis of eIF4A-targeted therapy, linking translational inhibition to innate immune activation, and provide a biomarker framework to guide future clinical trials combining zotatifin with chemotherapy in TNBC. Citation Format: N. Zhao, E. Kabotyanski, J. Lei, A. Saltzman, M. Lewis, J. Yang, J. Rosen. Targeting eIF4A unleashes type I IFN immunity in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-01.