Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor prognosis. The early pre-malignant events that lead to TNBC remain elusive, largely due to a lack of tractable models that recapitulate stepwise tumor initiation in a natural tissue context. Here, we use a spontaneous mouse model with mammary-specific deletion of Brca1 and Trp53, which develops TNBC, together with single cell RNA sequencing and multi-color flow cytometry to investigate the cellular and molecular landscape of the pre-tumoral mammary glands. Strikingly, the microenvironmental changes occur before any detectable tumors, driven by Brca1/Trp53 loss and MYC activation in luminal epithelial cells. Although macrophages remained proportionally comparable in the pre-tumoral lesions, their interactions with other populations were much reinforced. Brca1/Trp53 loss generated unstable genome and DNA fragment due to impaired DNA damage repair, which was sensed by macrophages and triggered type I interferon expression. The reprogrammed macrophages expressed IL-10 to paralyze cytotoxic T cells, TGFβ to target mast cells, and CD137L to stimulate Tregs, contributing to a favorable tumor-initiating niche. The rewired macrophages were stimulated by mutant luminal progenitor-derived CSF1 and were continuously recruited via CCR1-CCL3/5 axis. Such remodeling of mammary gland milieu allows breast tumor formation. After tumor was established, neutrophils were expanded and recruited to the developed tumors, circulation, and the lungs regardless of metastasis outgrowth. The neutrophils were amplified by elevated CSF3 from abnormal luminal progenitors and SAA2 from secretory alveolar cells in early lesions, which created chronic inflammation and facilitated the establishment of pre-metastatic niche in the lungs. Together, our study establishes a stepwise model of immune remodeling preceding TNBC onset and uncovers macrophage-centered signaling as a mechanistic axis linking genetic instability to a tumor-permissive niche. These findings provide insights into early intervention targets in high-risk breast cancer. Citation Format: LUQI HUANG, James A. Miller, Hanisah MK, Bernett Lee, Su I-hsin. Early Immunosuppressive Landscape Shaped by BRCA1/p53 Loss in Early Pre-Malignant Mammary Glands Permits Tumor Development abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P10.
Huang et al. (Thu,) studied this question.