Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8 + T cell metabolic fitness and function in tumors

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8⁺ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8⁺ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca²⁺-ATPase SERCA2, facilitating the mitochondrial Ca²⁺ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca²⁺ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca²⁺ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8⁺ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8⁺ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.