Immunosuppressive microenvironment restrains chemotherapy efficacy in liver metastases of triple-negative breast cancer

This study investigates the role of the immune microenvironment in the efficacy of chemotherapy for triple-negative breast cancer (TNBC) liver metastases compared to primary tumors. Using mouse models, we assessed chemotherapeutic efficacy and characterized intratumoral T lymphocytes and macrophages via RNA sequencing, immunohistochemistry, and flow cytometry. We found that liver metastases had a less effective response to chemotherapy compared to subcutaneous tumors, linked to reduced CD8+ T cell infiltration and macrophage activation. Chemotherapy induced an immunosuppressive shift, with neutrophil extracellular traps (NETs) accumulating in liver metastases and macrophages and T cells showing impaired functionality in the primary tumors. Combining macrophage activators or NETs inhibitors with chemotherapy improved outcomes. Our findings highlight the importance of tumor site-specific immune microenvironmental differences in chemotherapy responses and suggest that targeted therapies could enhance chemotherapy efficacy. Overall design: To assess the efficacy of chemotherapy, mouse models harboring TNBC liver metastases or primary tumors were utilized. RNA sequencing (RNA-seq) was conducted to analyze gene expression profiles in both subcutaneous tumors and liver metastases before and after chemotherapy treatment.