空间蛋白质组学揭示血管系统和免疫调节以克服乳腺癌中的多柔比星耐药

Therapeutic resistance hinders the efficacy of single-agent cancer treatments, often mediated by the tumor microenvironment. Significant endothelial cell enrichment following local doxorubicin treatment has been proposed as a resistance mechanism in breast cancer. Here, we apply the tumor vasculature normalization principle using an anti-angiogenic drug combination delivered locally using the high-throughput multiplex implantable microdevice assay in mouse models of breast cancer. Spatial single-cell proteomic profiling paired with unsupervised learning methods confirmed doxorubicin-mediated pro-angiogenic changes, including pericyte detachment and sprouting angiogenesis. A combination with cabozantinib depleted endothelial cells and increased tumor antigenicity by inducing immunogenic cell death with recruitment of leukocytes including neutrophils, and T cells. Leveraging this immune modulatory activity, we tested a systemic triple combination with anti-PD1 immunotherapy, which led to a significant and complete tumor regression. Our study demonstrates a rational drug combination that improves doxorubicin efficacy to overcome microenvironment-driven resistance for long-term breast cancer control.