靶向溴结构域和超末端蛋白重编程巨噬细胞并抑制乳腺癌进展

ZBC260 efficacy was evaluated in immunocompetent BALB/c mice bearing D2A1 tumors. NK cells or macrophages were depleted to determine their contribution to BETd response. In vitro , primary murine NK cells, bone marrow-derived macrophages, and THP-1, NK-92 MI, SUM-149, and D2A1 cells were used for co-culture, transwell migration, phagocytosis, qPCR, ELISA, and flow cytometry assays. Single-cell RNA sequencing (scRNA-seq) was performed using 10x Genomics 3' sequencing and analyzed with Seurat. RESULTS AND DISCUSSION: ZBC260 inhibited tumor growth in SCID mice but not in NOD-SCID mice, with impaired macrophages and partially compromised NK cells, implicating the innate immune system. To assess the contribution of innate immune cells to BETd efficacy, we depleted NK cells or macrophages in immunocompetent BALB/c mice with D2A1 tumors and treated with ZBC260 or vehicle. Immune depletion studies revealed macrophage loss partially attenuated anti-tumor and anti-CSC effects, highlighting their critical role. To understand the impact of BETd on TME populations, we performed single-cell RNA sequencing, which identified myeloid cells as the predominant population. BETd reduced MRC1⁺immunoregulatory tumor-associated macrophages and enriched CD74+ antigen-presenting macrophages, with upregulated phagosome pathways and enhanced Stat1 activation. In vitro , BETd downregulated M2-associated markers, promoted macrophage phagocytosis, induced tumor cell apoptosis, and inhibited macrophage-driven CSC formation. Collectively, these findings demonstrate that BETd ZBC260 reshapes the TME and reprograms macrophages toward an anti-tumor phenotype, highlighting its translational potential for breast cancer therapy.

Collectively, these findings demonstrate that BETd ZBC260 reshapes the TME and reprograms macrophages toward an anti-tumor phenotype, highlighting its translational potential for breast cancer therapy.