T细胞的代谢健康对其生命力至关重要，这在很大程度上取决于线粒体的行为。肿瘤浸润的T细胞中，线粒体行为的本质尚不清楚。在本研究中，我们展示了线融合素-2（MFN2）的表达与多种癌症预后呈正相关。在CD8+ T 细胞中遗传消除 Mfn2抑制了线粒体的代谢和功能，促进了肿瘤的进展。在肿瘤浸润的 CD8+ T 细胞中，MFN2通过与ER嵌入的 Ca2+-ATPase SERCA2相互作用，增强了线粒体-内质网（ER）接触，有助于高效线粒体代谢所需的线粒体 Ca2+内流。 MFN2 刺激了 SERCA2 的 ER Ca2+回收活性，从而防止了过多线粒体 Ca2+的积累和细胞凋亡。通过提高 CD8+ T 细胞中 MFN2 的表达来提升线粒体-ER 接触，可以改善癌症免疫治疗的效果。因此，我们揭示了一个调节肿瘤浸润的 CD8+ T 细胞代谢健康的细胞器交流的接合和缓冲机制，并强调增强 MFN2 的表达以优化 T 细胞功能的治疗潜力。

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.