Ribosomal RNA Biosynthesis Functionally Programs Tumor-Associated Macrophages to Support Breast Cancer Progression

Abstract Macrophages are important cellular components of the innate immune system, serving as the first line of immune defense. They are also among the first immune cells to be reprogrammed by the evolving tumor milieu into tumor-supportive macrophages that facilitate tumor progression and promote therapeutic evasion. Here, we uncovered that macrophages from preneoplastic breast lesions were enriched for ribosome biosynthesis genes, indicating that this is an early event that is maintained in the tumor tissue. Furthermore, following treatment with irradiation or chemotherapy, breast tumors featured an abundance of tumor-supporting macrophages that displayed an enrichment of signatures of ribosomal RNA expression and ribosome biosynthesis. Consistently, rRNA synthesis was increased in tumor-supportive macrophages. In preclinical models of mammary cancer, a low dose of the RNA biogenesis inhibitor BMH-21 converted pro-tumor macrophages to tumor-suppressive macrophages and supported an inflammatory tumor microenvironment. Inhibition of rRNA transcription stimulated a nucleolar stress response that activated the p53 and NF-κB pathways, which orchestrated impaired ribosome biogenesis checkpoint signaling that induced an inflammatory program in macrophages. Finally, inhibiting ribosome biogenesis augmented the effectiveness of neoadjuvant therapy. Together, these findings provide evidence that ribosome biogenesis is a targetable dependency to reprogram the tumor immune microenvironment.