Microglial TBK1 Signaling Promotes Breast Cancer Brain Metastasis

Breast cancer brain metastasis (BCBM) is the most common and lethal form of brain tumor, marked by abundant infiltration of tumor-associated microglia (TAMG). TAMG can promote the seeding and growth of metastatic breast cancer cells, highlighting the need to elucidate the molecular mechanisms underlying their function to enable the development of effective strategies to target TAMG in BCBM. In this study, using tumor samples from patients with BCBM and mouse models, and in vitro microglia culture systems, we demonstrated that TANK-binding kinase 1 (TBK1) signaling is enriched and activated in TAMG. TBK1 inhibition in TAMG reduced epithelial-mesenchymal transition, migration, invasion, and proliferation of breast cancer cells. Through integrated analyses of transcriptomic profiles, patient survival data, and secretome dataset, followed by experimental validation, GM-CSF was identified as the key secreted protein mediating TBK1-regulated metastatic behaviors of breast cancer cells. Pharmacologic inhibition of TBK1 in BCBM mouse models reduces BCBM and extends survival. Together, these data indicate that TBK1 signaling in TAMG contributes to BCBM and, along with its downstream effector GM-CSF, represents a promising therapeutic target for this deadly disease. SIGNIFICANCE: Enrichment and activation of TBK1 in tumor-associated microglia upregulates GM-CSF to promote metastatic properties of breast cancer cells, highlighting TBK1 inhibition as a potential therapeutic opportunity for treating breast cancer brain metastasis.