Genetically engineered macrophages delivering TRAIL targeting the Wnt/β-catenin pathway to induce cytotoxicity against TNBC.

Triple-negative breast cancer (TNBC) is a highly aggressive cancer subtype that lacks effective targeted therapies, posing significant challenges in its treatment. Engineered macrophages have emerged as promising tools for drug delivery and immunotherapy in cancer treatment. In this study, we developed a drug delivery strategy based on genetically modified macrophages. These macrophages were engineered in two ways to continuously secrete the apoptosis signal activator TRAIL, including monomeric TRAIL (Mono-TRAIL) and trimeric TRAIL (Tri-TRAIL). Engineered macrophages, particularly Tri-TRAIL-M, were found to promote M1 macrophage polarization within the tumor microenvironment (TME), thereby enhancing antitumor immune responses. Simultaneously, the engineered macrophages significantly inhibited the Wnt/β-catenin signaling pathway in TNBC cells and induced G2/M phase cell cycle arrest. In an in vivo TNBC model, Tri-TRAIL-M effectively suppressed tumor growth, highlighting its therapeutic potential. These findings suggest that TRAIL-secreting engineered macrophages, especially Tri-TRAIL-M, provide a promising strategy for TNBC cytotoxicity. This approach opens new avenues for macrophage-based therapies in TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02394-7.