The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breast-to-brain metastasis

The brain environment is uniquely specialized to protect its neuronal tissue from excessive inflammation by tightly regulating adaptive immunity. However, in the context of brain cancer progression, this regulation can lead to a conflict between T cell activation and suppression. 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-programmed cell death protein 1 (PD1) therapy was effective 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.