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

Abstract Glial cells play a critical role in shaping the tumor microenvironment in brain metastases (BM), 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 cross-talk 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 interglial communication. Unique ligand–receptor pairs, including OSM–OSMR, CCL4–CCR5, CXCL16–CXCR6, IL1A/B–IL1R, and TNF–TNFR, functioned as key drivers of interglial cross-talk, which sustained the tumor-supportive niche. Therapeutic targeting of CCL4–CCR5 signaling with maraviroc, an FDA-approved antiviral drug, significantly reduced BM 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 BMs. Significance: Glial cells are masterminds of brain metastasis that orchestrate tumor-supportive signals and can be targeted with maraviroc to disrupt the metastatic niche as a safe and effective strategy to halt metastatic progression.