Cross-species transcriptomic integration reveals a MIRO1-mediated macrophage-T cell axis in glioma

Life Sci Alliance. 2026 May 13;9(8):e202603749. doi: 10.26508/lsa.202603749. Print 2026 Aug.

ABSTRACT

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 an MIRO1-binding compound and bulk RNA sequencing of human glioma resections treated with the same compound ex vivo. Cross-species transcriptomic integration reveals an MIRO1-responsive program in the TME. Among shared targets, we identify PARP11/Parp11 as a consistently up-regulated gene in glioma, which is down-regulated after 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 Parp11 and Pdl1 (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 study provides a transcriptomic framework for understanding mitochondria-immune crosstalk and nominates MIRO1-PARP11 as a potential effector axis of brain immune dysfunction.

PMID:42128668 | PMC:PMC13171295 | DOI:10.26508/lsa.202603749