Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity.

ABSTRACT: 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 the brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to the M2 phenotype via the α2β1 integrin/nuclear factor 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 BrM. Col003, an inhibitor disrupti

SUBMITTER: Wang L 

PROVIDER: S-EPMC11149409 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature