Center for Engineered Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA.
Nat Nanotechnol. 2022 Jan;17(1):98-106. doi: 10.1038/s41565-021-01000-4. Epub 2021 Nov 18.
Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.
癌症通过逃避免疫系统而进展。阐明各种免疫逃避策略是寻找下一代癌症免疫疗法的关键步骤。在这里，我们报告癌细胞可以通过物理纳米管从免疫细胞中劫持线粒体。线粒体对于免疫细胞的代谢和激活至关重要。通过使用场发射扫描电子显微镜、荧光标记的线粒体转移示踪和代谢定量，我们证明了免疫细胞到癌细胞的纳米管介导的线粒体转移在代谢上赋予了癌细胞能量，并耗尽了免疫细胞。抑制纳米管组装机制可显著减少线粒体转移并防止免疫细胞耗竭。联合使用法尼基转移酶和香叶基香叶基转移酶 1 抑制剂，即 L-778123，它部分抑制纳米管形成和线粒体转移，以及程序性细胞死亡蛋白 1 免疫检查点抑制剂，可改善侵袭性免疫功能健全的乳腺癌模型中的抗肿瘤效果。纳米管介导的线粒体劫持可能成为开发下一代癌症免疫治疗药物的新靶标。
