Cross-species spatial profiling links progranulin to an immune suppressive niche in brain metastasis

Abstract Immune checkpoint inhibitors (ICI) have revolutionized the treatment of brain metastasis (BM), demonstrating intracranial response rates and durability not previously seen with other therapies. However, approximately 50% of patients do not respond to ICI, and the brain-specific interactions that shape anti-tumor immunity remain poorly understood. We profiled five syngeneic BM models using spatial transcriptomics, identifying myeloid-rich niches enriched for interferon-responsive and disease-associated microglia (DAM)-like programs. Ligand-receptor colocalization analyses identified progranulin (PGRN) as a candidate mediator of these niches. Host- or tumor-cell Grn loss reduced BM burden, and Grn -deficient macrophages exhibited altered metabolic programs and tumor-cell engulfment in vitro. Across independent human BM datasets, GRN expression was associated with conserved lysosomal and DAM-like myeloid programs, and GRN -high myeloid regions colocalized with immunosuppressive signatures and dysfunctional CD8+ T cell states. These cross-species findings identify PGRN as a candidate mediator of the BM immune niche and support further investigation of its therapeutic relevance. Highlights A multi-model spatial atlas resolves myeloid niches in both preclinical models of brain metastases and human patient tissues Host- and tumor-cell progranulin support brain metastatic growth Progranulin associates with lysosomal function and disease-associated myeloid states in brain metastasis Human progranulin-rich myeloid niches colocalize with dysfunctional cytotoxic T cells in brain metastasis Graphical Abstract