肿瘤细胞治疗研究
英文原题：GBP6 maintains mitochondrial bioenergetics to promote immune evasion from NK cells in cervical cancer.
GBP6 maintains mitochondrial bioenergetics to promote immune evasion from NK cells in cervical cancer.
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代谢重编程和免疫逃逸是癌症进展的核心标志；然而，线粒体代谢如何塑造免疫逃逸仍不清楚。
代谢重编程和免疫逃逸是癌症进展的核心标志；然而，线粒体代谢如何塑造免疫逃逸仍不清楚。在此，我们鉴定出 GBP6 是一个与侵袭性宫颈癌相关的肿瘤内在线粒体因子。GBP6 在高危肿瘤中富集，并与不良临床结局相关。敲低 GBP6 可抑制肿瘤细胞增殖并促进细胞死亡。机制上，GBP6 定位于线粒体，与 TACO1 相互作用，并支持呼吸链复合体 IV 的完整性和活性。GBP6 缺失会破坏线粒体生物能量学，降低膜电位和 NADPH 可用性，增加 ROS 产生，并损害 GSH-GPX4 抗氧化轴，从而促进脂质过氧化和铁死亡相关细胞死亡。这种线粒体氧化还原应激通过 ROS-NF-κB 信号诱导 ICAM-1 表达，增强 NK 细胞黏附、免疫突触形成和肿瘤细胞杀伤。在异种移植模型中，GBP6 缺失使肿瘤对过继转移的 NK 细胞敏感。这些发现表明 GBP6 是一个线粒体调节因子，将代谢适应性同宫颈癌中的固有免疫逃逸联系起来。
Metabolic reprogramming and immune evasion are central hallmarks of cancer progression; yet, how mitochondrial metabolism shapes immune escape remains unclear. Here, we identify GBP6 as a tumor-intrinsic mitochondrial factor associated with aggressive cervical cancer. GBP6 is enriched in high-risk tumors and correlates with poor clinical outcomes. GBP6 knockdown suppresses tumor cell proliferation and promotes cell death. Mechanistically, GBP6 localizes to mitochondria, interacts with TACO1, and supports respiratory complex IV integrity and activity. GBP6 depletion disrupts mitochondrial bioenergetics, reduces membrane potential and NADPH availability, increases ROS production, and compromises the GSH-GPX4 antioxidant axis, thereby promoting lipid peroxidation and ferroptosis-associated cell death. This mitochondrial redox stress induces ICAM-1 expression through ROS-NF-κB signaling, enhancing NK-cell adhesion, immune synapse formation, and tumor-cell killing. In xenograft models, GBP6 depletion sensitizes tumors to adoptively transferred NK cells. These findings identify GBP6 as a mitochondrial regulator linking metabolic fitness to innate immune evasion in cervical cancer.
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