Targeting the HSP47-Collagen Axis Inhibits Brain Metastasis by Reversing M2 Microglial Polarization and Restoring Anti-Tumor Immunity

Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to M2 phenotype via the α2β1 integrin/NF-κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8+ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8+ T cells and abolishes brain metastasis. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrMs-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression, and blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors. To elucidate the mechanism underlying that COL1 promotes M2 microglial polarization, we cultured BV2 cells in a 3D COL1 gel and then profiled gene expression by RNA-seq.