Brain metastases (BrM) carry a poor prognosis despite current standard-of-care treatments, including radiotherapy (RT). Thus, advancing our understanding of BrM biology is crucial for developing more effective treatments. Through comprehensive and integrated analyses of the tumor microenvironment (TME), we have previously shown that tumor-associated macrophages (TAMs) constitute a highly abundant immune cell type within BrM. Furthermore, we have found that TAMs in BrM are immunosuppressive, underscoring the importance of targeting these cells, including via CSF-1R inhibition.

To elucidate the role of TAMs in the response to RT, we conducted a series of in vivo experiments and functional assays. We evaluated RT alone versus RT combined with the CSF-1R inhibitor BLZ945 using tumor progression and survival as primary endpoints, complemented by functional assays to interrogate treatment-associated immune and tumor phenotypes.

Preliminary findings show an overall benefit of combining BLZ945 with RT compared with either treatment alone. Notably, the combination effect was driven by a subset of mice that achieved complete tumor regression and did not exhibit tumor rebound after discontinuation of CSF-1R inhibition, suggesting response heterogeneity and evident durable control in the responders.

Following this intriguing result, ongoing research is focused on defining how TAMs shape the response to RT and on identifying mechanisms underlying the responder versus non-responder phenotypes to inform biomarkers and rational combination strategies.