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Intercellular mitochondrial transfer from tumor cells enhances CD8⁺ T cell cytotoxicity via SPHK2-derived S1P signaling

ABSTRACT: Intercellular communication in the tumor microenvironment (TME) dictates the balance between cancer progression and immune control. While cancer cells often hijack resources from the stroma, whether immune cells can conversely acquire tumor organelles remains largely unexplored. Here, we demonstrate that tumor-infiltrating CD8+ T cells selectively acquire functional mitochondria from tumor cells via a TCR-independent, Trak1–Miro1-mediated contact mechanism. Strikingly, this mitochondrial transfer enhances CD8+ T cell cytotoxicity, driving increased Granzyme B and Perforin production. This process is fueled by tumor-mitochondria-derived sphingosine-1-phosphate (S1P), which activates S1PR1 signaling and receptor internalization within recipient T cells. Deficiency in tumor SPHK2 reduces mitochondrial S1P, impairing T cell function and promoting tumor progression. Our findings reveal the pivotal role of mitochondrial transfer in the regulation of anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE329367 | GEO | 2026/09/01

REPOSITORIES: GEO

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