BRCA1 deficiency programs a microglia-supported ferroptosis-resistant niche in breast cancer brain metastasis

Several mutations have been identified in triple-negative breast cancer (TNBC), including deleterious mutations in BRCA1 . Despite advances in understanding and managing BRCA1 -associated TNBC, the brain metastatic stage of this disease remains largely understudied. This study sought to identify genotype-specific tumor-microglia interactions that facilitate brain colonization and to develop a targeted, multimodal therapeutic strategy to disrupt this niche. We established the first isogenic in vivo models of BRCA1 -mutated and BRCA1 -restored BC brain metastasis (BC-BrM). Brain-tropic BC cell lines were generated through four rounds of in vivo selection. Tumor-microglia dynamics were evaluated using in vitro co-culture systems of migration, proliferation, and invasion assays. Clinically, we analyzed human datasets (METABRIC, TCGA, GSEA) to correlate BRCAness and p53 status with metastatic site. We engineered P-selectin-targeted PLGA-PEG nanoparticles (sNPs) encapsulating an SCD1 inhibitor (SCD1i) and a ferroptosis inducer, utilizing low-dose radiation to guide sNPs accumulation in BC-BrM. In a recent analysis of a human dataset, we found that the BRCAness score was higher in BrM than in other organ metastases of BC. BRCAness signatures were higher in primary BCs that later metastasized to the brain than in those that metastasized to other organs, and correlated with BrM potential. Using our spontaneous BRCA1 -mutated BC-BrM model, we confirmed that BRCA1 deficiency homes BC cells to the brain and worsens prognosis. Moreover, BRCA1 -deficient BC cells isolated from the spontaneous BC-BrM model, but not their BRCA1 -restored BC-BrM cell lines or parental counterparts, gained functional advantages when co-cultured with microglia, with significantly enhanced migration, proliferation, and invasion. This interaction was associated with ferroptosis resistance, consistent with an extrinsic antioxidant shield provided by the microglial niche. Concurrently, p53 inactivation drove an intrinsic metabolic addiction to SCD1-mediated fatty acid synthesis (FAS); consequently, brain-tropic cells exhibited heightened sensitivity to SCD1i. Integrating these insights, we sNPs to co-deliver SCD1i and ferroptosis inducers. We demonstrate that low-dose radiation upregulates P-selectin on the BrM vasculature, resulting in a significantly increased accumulation of sNPs in BrM compared to non-targeted controls, effectively overcoming the blood-brain barrier to target this synthetic lethal vulnerability. These findings establish a new paradigm where BRCA1 -mutated cells acquire a specialized capacity to exploit the microglial niche for ferroptosis resistance. By combining metabolic blockade of FAS with the induction of oxidative lethality via targeted sNPs, we provide a potent and clinically relevant precision strategy for treating BRCA1 -mutated BC-BrM.