Spatial Crosstalk Modeling of the Tumor Microenvironment Identifies CCR5-Mediated Glia-to-Glia Signaling as a Key Regulator of Brain Metastatic Progression

Glial cells play a critical role in shaping the tumor microenvironment in brain metastases, facilitating disease progression through complex tumor-glial cell and distinct glia-to-glia signaling pathways. To investigate these interactions, we performed RNA sequencing of astrocytes, microglia, and oligodendrocytes at various stages of brain metastatic progression, combined with spatial transcriptomics and cell-cell crosstalk analysis. Glial cells not only converged on tumor-promoting pathways such as RAS and Gap junction signaling in tumor cells but also engaged in distinct autocrine and paracrine signaling critical for inter-glial communication. Unique ligand-receptor pairs, including OSM-OSMR, CCL4-CCR5, CXCL16-CXCR6, IL1A/B-IL1R, and TNF-TNFR, functioned as key drivers of inter-glial crosstalk, which sustained the tumor-supportive niche. Therapeutic targeting of CCL4-CCR5 signaling with maraviroc, an FDA-approved antiviral drug, significantly reduced brain metastasis progression without exerting direct cytotoxic effects on tumor cells. These findings highlight a promising therapeutic strategy that focuses on modulating glial communication within the tumor microenvironment. By disrupting the supportive glial niche rather than targeting tumor cells directly, this represents a distinct and potentially less toxic approach for managing brain metastases.