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. 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.