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

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.