Abstract Brain metastases are a lethal complication of cancer, characterized by profound immunosuppression and limited systemic treatment options. Our studies identify cytomegalovirus (CMV) reactivation as a prevalent and clinically relevant modifier of the immunue environment in triple-negative breast cancer (TNBC) brain metastasis, with viral antigens detected in 89% of human brain metastases across tumor types. Using single-cell multi-omics and spatial transcriptomics on 50, 000+ cells from CMV-infected TNBC brain metastasis models, we constructed a comprehensive tumor-immune atlas demonstrating that CMV reshapes microglial and myeloid states toward immunosuppressive phenotypes. CMV reprograms homeostatic microglia into myeloid-derived suppressor-like cells, depleting tumor-surveillance microglia and organizing spatially clustered immunosuppressive niches. Mechanistically, CMV-infected microglia upregulate TGF-β and ARG1 to drive M2 polarization, while CMV-positive tumor cells increase expression of MMP17 to enhance blood-brain barrier invasion and IL27RA to promote immunosuppression. In addition, CMV-positive tumor cells secrete CXCL10, CCL2, and CXCL9 to recruit myeloid-derived suppressor cells, further amplifying the immunosuppressive network. Pharmacologic inhibition of CMV with the antiviral foscarnet suppresses tumor growth, restores antitumor immunity, and synergizes with capecitabine to prolong survival. Together, these findings suggest that CMV reactivation is a modifiable contributor to the immune dysfunction underlying TNBC brain metastasis and provide a mechanistic rationale for evaluating antiviral therapy as an immunomodulatory component of future treatment strategies. Citation Format: Hong Zhao, Wenjuan Dong, Shan Xu, Shiruo Wang, Akshjot Puri, Matthew Vasquez, Dongbing Gao, Xiaohui Yu, Johnny Cui, Johnson Lau, James Sampson, Caitlin Sannes, Jenny Chang, Stephen Wong. Cytomegalovirus reactivation orchestrates myeloid reprogramming to drive brain metastasis progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB256.
Zhao et al. (Fri,) studied this question.