Metastatic dissemination to the brain occurs in approximately one-third of patients with breast cancer (BC) and can lead to life-threatening neurological damage. Stereotactic radiosurgery (SRS), a standard-of-care treatment for brain metastasis (BrM), controls over 80% of targeted lesions. However, the emergence of new BrM lesions outside the irradiation field and the progression of extracranial disease limit median overall survival to just over one year. Therefore, there is an urgent need to develop more efficient therapies. To achieve this, it is crucial to understand how the local tumor microenvironment (TME) responds to treatment.

To study the changes in the BC-BrM TME, we used various in vivo studies, transcriptional analyses, and functional assays to directly compare orthotopic BC tumors with their BC-BrM counterparts.

Here, we show that while CD8+ T cells can infiltrate breast cancer-brain metastases, their anti-tumor cytotoxicity is locally suppressed in the brain. Conversely, CD8+ T cells exhibited tumoricidal activity in extracranial mammary lesions originating from the same cancer cells. Consequently, combined high-dose irradiation and anti-PD1 therapy was effective only in extracranial tumors, but not intracranial lesions. Transcriptional analyses and functional studies identified neutrophils and Trem2-expressing macrophages as key sources for local T cell suppression within the brain, providing rational targets for future therapeutic strategies.

In this study, we show that while CD8+ T cells infiltrate BC-BrM, they lack anti-tumor cytotoxicity even under T cell-stimulating conditions. Single-cell profiling and ex-vivo functional assays identified BrM-infiltrating neutrophils and Trem2+ monocyte-derived macrophages and microglia (collectively termed tumor-associated macrophages, TAMs) as key sources of local T cell suppression.