SIRPα Protein Promotes Brain Metastasis in Triple-Negative Breast Cancer Through Mitochondrial Fission and Fibronectin-Mediated Microglial Suppression

The study combined analysis of human TNBC datasets and resected brain metastases with cell-line and xenograft experiments. SIRPα overexpression fragmented mitochondria via Drp1 activation, increasing cell motility, and upregulated fibronectin secretion that desensitized microglia to inflammatory cues. Reducing SIRPα reversed both phenotypes and lowered intracranial tumor burden across multiple models. These intracellular effects extend the known CD47-SIRPα axis beyond macrophage checkpoint blockade.

Prior work has linked mitochondrial fission to metastatic potential in other solid tumors, yet few studies have connected this process to brain-specific immune evasion in TNBC. The current findings integrate energy metabolism, extracellular matrix remodeling, and innate immune suppression into a single pathway, explaining why TNBC disproportionately seeds the brain where microglia dominate the myeloid compartment.

Translation will require selective SIRPα antagonists that penetrate the blood-brain barrier and spare systemic immune surveillance. Biomarker-driven trials stratifying patients by tumor SIRPα expression could test whether dual intracellular and microenvironmental targeting improves progression-free survival over existing HER2- and PD-1-directed approaches.

Next steps include orthotopic patient-derived xenograft validation and toxicology studies of brain-penetrant SIRPα inhibitors ahead of first-in-human testing.