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Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expansion, and rebound in response to immunotherapy to reject metastatic malignances. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate that peripheral CX3CR1+CD8+T cells with low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy in patients with large tumor burden portraying their functional resiliency. Furthermore, CX3CR1+CD8+T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS), and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysisindependent manner while concurrently curtailing excessive ROS in activated CD8+T cells; and expands CX3CR1+NKG7+effector CD8+T cells with enhanced cytotoxicity. Importantly, transfection ofME1mRNA promotes tumoricidal activity in CD8+T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion.Graphical abstractHighlightsCX3CR1+and low Dy m identify functional resilient CD8+T cells.Resilient CD8+T cells are highly cytotoxic and have less ROS.Resilient CD8+T cells express more ME1 that can balance extra ROS.ME1 overexpression can promote CTL function of CD8+T cells.