Cross-Species Transcriptomic Integration Reveals a Conserved, MIRO1-Mediated Macrophage-to-T Cell Signaling Axis Driving Immunosuppression in Glioma.

Mitochondrial regulators are increasingly recognized for their influence on immune signaling within the tumor microenvironment (TME). In glioma, where immunosuppression limits therapeutic efficacy, we investigate how targeting the mitochondrial protein MIRO1 alters the TME. We combine single-nucleus RNA sequencing of murine gliomas treated in vivo with a MIRO1-binding compound and bulk RNA sequencing of human glioma resections treated with the same compound ex vivo. Cross-species transcriptomic integration reveals a conserved MIRO1-responsive program in the TME. Among shared targets, we identify as a consistently upregulated gene in glioma that is downregulated following MIRO1-binding compound treatment in both human and mouse gliomas. Cell-cell communication analysis shows that a specific cluster of macrophages (MAC1), which exhibits robust and (encoding PD-L1) expression, sends immunosuppressive signals to CD8+ cytotoxic T cells, and may receive prostaglandin E₂ signals from another cluster of macrophages (MAC4). Targeting MIRO1 eliminates this cell circuitry and reduces the tumor cell population. Our data suggest MAC4 as the originating MIRO1-driven cell cluster, which relays a macrophage-to-T cell signaling axis that may contribute to immune suppression in glioma through PARP11 regulation. Our study provides a transcriptomic framework for understanding mitochondria-immune crosstalk in the brain TME and nominates MIRO1 PARP11 as a potential effector axis of immune dysfunction.