This prospective observational cohort study investigates the subset-specific metabolic adaptation and functional remodeling of cytotoxic γδT cells in critically ill patients with and without sepsis. Emerging evidence indicates that γδT cells, as a bridge between innate and adaptive immunity, play a critical role in early anti-infection defense during sepsis. However, the functional status and underlying regulatory mechanisms of cytotoxic γδT cells in septic patients remain incompletely understood. Our preliminary single-cell transcriptomic analysis revealed that cytotoxic γδT cells from septic patients exhibit significant alterations in cytotoxicity-associated molecules (GZMB, PRF1, GNLY) and mitochondrial oxidative phosphorylation (OXPHOS) pathway genes, particularly COX6C, which correlates with cytotoxic effector molecule expression. This study aims to systematically characterize the proportion, cytotoxicity, and mitochondrial metabolic function of circulating cytotoxic γδT cells across three cohorts: healthy controls, critically ill non-septic patients, and critically ill septic patients. By integrating flow cytometry, mitochondrial function assays, and functional validation experiments, we seek to elucidate the role of COX6C-mediated mitochondrial metabolic abnormalities in cytotoxic γδT cell dysfunction, providing theoretical basis for understanding immune dysregulation in sepsis and identifying novel therapeutic targets.