Abstract P2-02-15: Engineered macrophages secreting TRAIL achieve immunotherapy for triple-negative breast cancer by inhibiting the Wnt/β-catenin signaling pathway

Abstract Macrophages play a critical role in the body's defense against cancer by phagocytosing tumor cells, presenting antigens, and activating adaptive T cells. However, macrophages are intrinsically incapable of delivering targeted cancer immunotherapies. Engineered adoptive cell therapy introduces new targeting and antitumor capabilities by modifying macrophages to enhance the innate immune response of cells and improve clinical efficacy. TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. In this study, we constructed engineered macrophages secreting mono-TRAIL and tri-TRAIL via viral transfection. The results showed that both types of TRAIL-secreting engineered macrophages could significantly kill triple-negative breast cancer (TNBC) cells and inhibit the proliferation of TNBC cells. The tri-TRAIL-secreting engineered macrophages (Tri-TRAIL-M) exhibited a more significant tumor-suppressive effect compared to the mono-TRAIL-secreting engineered macrophages (Mono-TRAIL-M). Additionally, the study results indicated that TRAIL-secreting engineered macrophages induced the M1 phenotype in macrophages by upregulating DR4 and downregulating DR5 expression. TRAIL, upon entering TNBC cells, could inhibit the tumor cell cycle by suppressing the Wnt/β-catenin signaling pathway. In conclusion, the tri-TRAIL-secreting engineered macrophages provide a novel strategy for constructing engineered macrophages for the immunotherapy of triple-negative breast cancer. Citation Format: Chuangui Song. Engineered macrophages secreting TRAIL achieve immunotherapy for triple-negative breast cancer by inhibiting the Wnt/β-catenin signaling pathway [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-02-15.