Abstract PS2-12-24: Ifitm1 influences natural killer cell-mediated cytotoxicity by modulation of hla-class i expression in triple-negative breast cancer cells

Abstract Interferon (IFN) activates the Janus kinase (JAK)/signal transducer and activator of transcription signaling pathway, resulting in induction of IFN-stimulated genes such as IFN-induced transmembrane protein 1 (IFITM1). Previous studies have shown that the overexpression of IFITM1 is associated with a poor prognosis in triple-negative breast cancer (TNBC); however, the mechanisms by which IFITM1 contributes to oncogenesis in TNBC are unclear. This study explored the mechanism by which IFITM1 induces tumorigenesis in TNBC. We established two stable cell lines: IFITM1-overexpressing cell line (MB-231-IFITM1-OE) and IFITM1 knockdown cell line (BT-20-IFITM1-KD). The transcriptional activity of β-catenin and the cytotoxic activity of natural killer (NK) cells were evaluated using the luciferase assay and the lactate dehydrogenase cytotoxicity assay. Knockdown of IFITM1 in BT-20 cells reduced cell proliferation and ectopically expressed IFITM1 in MB-231 cells increased cell proliferation. RNA sequencing analysis revealed that IFITM1 expression positively correlated with the Wnt/β-catenin signaling pathway and NK cell-mediated cytotoxicity. MB-231-IFITM1-OE cells showed increased β-catenin transcriptional activity and NK cell cytotoxic activity compared with controls, while transient knockdown of IFITM1 in MB-231-IFITM1-OE cells led to a decrease in β-catenin transcriptional activity and NK cell cytotoxic activity. MB-231-IFITM1-OE cells exhibited decreased HLA class I expression, which may have contributed to their increased susceptibility to NK cell-mediated lysis. β-catenin or JAK inhibitor reduced NK cell-mediated cytotoxicity via upregulation of HLA class I in TNBC cells. In conclusion, IFITM1 overexpression was associated with Wnt/β-catenin signaling and NK cell-mediated cytotoxicity via downregulation of HLA class I in TNBC cells, suggesting that IFITM1 might have immunoregulatory effects on the tumor microenvironment. Citation Format: H. Won, H. Lee, C. Park, K. Kang, S. Hong, Y. Ahn, Y. Ko. Ifitm1 influences natural killer cell-mediated cytotoxicity by modulation of hla-class i expression in triple-negative breast cancer cells [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 PS2-12-24.