Spatial crosstalk modeling of the tumor microenvironment uncovers CCR5-mediated glia-to-glia signaling as a key regulator of brain metastases

Glial cells play a critical role in shaping the tumor microenvironment in brain metastases, facilitating disease progression through complex tumor-glial and distinct glia-to-glia signaling pathways. To investigate these interactions, we conducted RNA sequencing of astrocytes, microglia, and oligodendrocytes at various stages of brain metastasis progression, combined with spatial transcriptomics and crosstalk analysis using the CCCExplorer tool. Our analysis uncovered that while glial cells converge on tumor-promoting pathways such as Ras and Gap junction signaling in tumor cells, they also engage in distinct autocrine and paracrine signaling critical for their own communication. Unique ligand-receptor pairs including OSM-OSMR, CCL4-CCR5, CXCL16-CXCR6, IL1A/B-IL1R, and TNF-TNFR were identified as drivers of glial crosstalk, which sustains the tumor-supportive niche. Targeting CCL4-CCR5-mediated glial signaling with maraviroc, an FDA-approved antiviral drug, reduced brain metastasis progression by 62% (p=0.004) without direct cytotoxicity to tumor cells. These findings highlight the novelty of targeting distinct glial autocrine and paracrine signaling as a therapeutic approach, shifting the focus from tumor cells to disrupting the glial niche that supports brain metastasis growth.