In addition to the initial challenge of T-cells infiltrating the tumors, ICB must overcome several obstacles, including tumor-infiltrating lymphocyte (TIL) exhaustion, the upregulation of inhibitory receptors and epigenetic modifications, metabolic adaptations resulting in nutrient deficits, impaired translocation of GLUT1 to the cell surface, the downregulation of glycolytic enzymes, GAPDH and ENO-1, and dysregulated and fragmented mitochondria with increased ROS generation [222,223,224,225]. The gene discussed is ENO1; the disease is neoplasm.