Tumor-derived mitochondria enhance CD8+ T cell cytotoxicity through SPHK2-dependent S1P signaling

Abstract

Intercellular organelle exchange is increasingly recognized as a feature of the tumor microenvironment, but whether tumor-derived mitochondria functionally shape anti-tumor T cell immunity remains unclear. Here we show that tumor-infiltrating CD8+ T cells acquire functional mitochondria from tumor cells through a contact-dependent, TCR-independent mechanism requiring the mitochondrial trafficking machinery Trak1-Miro1. Transferred tumor mitochondria enhanced CD8+ T cell effector activity, increasing cytotoxic molecule expression and tumor-cell killing. Mechanistically, tumor-derived mitochondria carried sphingosine-1-phosphate (S1P), which engaged S1PR1 signaling in recipient T cells. Tumor-specific deletion of Sphk2 diminished mitochondrial transfer-associated T cell activation, impaired CD8+ T cell effector function, and accelerated tumor progression in vivo. These findings reveal tumor-to-T cell mitochondrial transfer as an unexpected immunostimulatory circuit in the TME and identify mitochondrial SPHK2-S1P signaling as a regulator of CD8+ T cell anti-tumor function.