Cancer-intrinsic SIRPα Signaling Triggers Mitochondrial Fission and Immune Tolerance to Promote TNBC Breast-to-Brain Metastasis.

BACKGROUND: Triple negative breast cancer (require) new treatment strategies due to poor responses to current therapies. While myeloid SIRPα mediates immunosuppression, its cancer intrinsic role remains poorly understood. METHODS: Human breast cancer scRNAseq profiles were used to examine SIRPα expression across different cell populations and subtypes. TNBC brain-tropic cells were injected into the mouse mammary fat pad for the orthotopic tumor model, and intracardiac-injected for brain metastasis models. Bulk RNA sequencing was used to determine SIRPα-regulated pathway. Stably SIRPα overexpressed and knockout TNBC cell lines were established to determine SIRPα intracellular regulation. Digital spatial profiling was utilized to investigate the orthotopic and brain metastasis tumor immune microenvironment. RESULTS: Human single-cell data showed that SIRPα levels increased in malignant TNBC epithelial cells. We observed that SIRPα is upregulated in patient breast-to-brain metastatic lesions. SIRPα is overexpressed in TNBC brain-tropic cells compared to parental cells. Bulk RNA-Seq showed that targeting SIRPα affects genes involved in mitochondrial dynamics, and that SIRPα upregulates mitochondrial fission and induces metastasis through the SHP2/Erk/Drp1 signaling pathway. In vivo, overexpression of SIRPα in cancer cells significantly increases TNBC systemic metastasis. Next, spatial proteomics revealed changes in the immune microenvironment associated with the SIRPα-regulated ECM protein fibronectin. Fibronectin induces microglial tolerance by impairing inflammatory signaling and metabolic reprogramming, allowing cancer to escape microglial immunosurveillance. Most importantly, SIRPα inhibition reduced TNBC brain metastatic lesions in mouse metastasis models. CONCLUSION: : Cancer-intrinsic SIRPα promotes TNBC brain metastasis through increased mitochondria fission and triggering microglia tolerance, and targeting SIRPα reduces brain metastasis.