ENO2 (enolase 2), also known as neuron-specific enolase (NSE), is a glycolytic enzyme catalyzing the reversible conversion between 2-phosphoglycerate and phosphoenolpyruvate 1. As a neuron-specific isoform expressed during neural differentiation, ENO2 serves as a highly specific marker for neurons and neuroendocrine cells 1. Beyond its canonical glycolytic function, ENO2 plays critical roles in metabolic reprogramming across multiple cancer types. ENO2 overexpression drives neuroendocrine differentiation and promotes malignant behavior in colorectal cancer by generating phosphoenolpyruvate (PEP), which functions as an endogenous HDAC1 inhibitor to activate β-catenin signaling 2. In cholangiocarcinoma, ENO2 expression is upregulated through the USP21/HSP90/HIF1A axis to promote aerobic glycolysis and chemotherapy resistance 3. Similarly, in gastric cancer, ENO2 activation by the METTL3/HDGF pathway enhances glycolysis and metastasis 4. ENO2-driven glucose metabolism sustains 3D tumor spheroid growth across lung and breast cancer models regardless of nutrient conditions 5. Clinically, ENO2 serves as a predictive biomarker for treatment resistance and disease prognosis across neuroendocrine tumors, small cell lung cancer, and neuroblastoma 1. Additionally, ENO2+ nanoparticles released from neural cells exposed to CAR T cell-derived vesicles may contribute to immune effector cell-associated neurotoxicity syndrome pathogenesis 6.