Ribosomal RNA biosynthesis functionally programs tumor-associated macrophages in breast cancer

Macrophages are among the 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 support tumor progression and promote therapeutic evasion. Unexpectedly, we uncovered that macrophages from preneoplastic breast lesions were enriched for ribosome biosynthesis genes evidencing that this is an early event that is maintained in the tumor tissue. Furthermore, following treatment with irradiation or chemotherapy, breast tumors demonstrated an abundance of tumor-supporting macrophages that displayed an enrichment of signatures of ribosomal RNA expression and ribosome biosynthesis. In alignment with this, rRNA synthesis was increased in tumor-supportive macrophages. In preclinical models of mammary cancer, a low dose of the RNA biogenesis inhibitor BMH-21 pivoted pro-tumor macrophages to macrophages with antitumor potential and supported an inflammatory tumor microenvironment. This pivot was accomplished by p53-NF-κB-orchestrated impaired ribosome biogenesis checkpoint signaling that activated an inflammatory program in macrophages. Finally, inhibiting ribosome biogenesis augmented the effectiveness of neoadjuvant therapy underscoring unexpected and unprecedented evidence that ribosome biogenesis is a targetable dependability to reprogram the tumor immune microenvironment.