Background: Young age is an independent risk factor for the development of breast cancer brain metastases (BM). Prior work showed that 17B-estradiol (E2), the predominant premenopausal hormone, promotes BM of tumors intrinsically unresponsive to E2, in part through modulating estrogen receptor-alpha expressing (ERalpha) glial cells. However, how E2 reshapes the brain tumor microenvironment (TME), particularly microglia-mediated immunity, and its impact to BM progression remains unclear. Methods: scRNA sequencing and multiparametric flow cytometry were used to define the impact of E2 and E2-suppression on brain immune-cell populations across different stages of BM progression using spontaneous and experimental models of BM. Depletion of microglia and T cell co-cultures were used to study the microglia role in E2-induced BM. The effects of E2-suppression alone or in combination with whole brain radiotherapy were tested in preclinical models mimicking late-stage BM. Results: E2 repressed immune surveillance and immune activation programs in microglia from early to late stages of brain metastatic progression, suppressing recruitment of effector immune cells to BM. Estrogen suppression, in turn reactivated anti-tumoral signaling in microglia and increased recruitment of effector immune cells to the brain. Microglia from E2-stimulated BM-bearing mice showed decreased ability to induce interferon cytotoxic function and expansion of activated T cells. Conversely, E2-suppression reactivated an effective anti-tumoral response and synergized with RT to significantly decrease BM progression. Conclusion: These findings reveal a previously unrecognized mechanism by which E2 accelerates BC-BM progression through microglial immunosuppression and support evaluation of endocrine therapie