Abstract

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.