Abstract
Tumor progression is characterized by profound metabolic alterations and dynamic interactions within the tumor microenvironment (TME), which enable rapid proliferation, immunoinvasion, and metastasis. The sympathetic nervous system (SNS), which has been best known for its role in stress regulation, has emerged as a critical regulator of tumor metabolism. The SNS influences glucose, lipid and glutamine metabolism in tumor cells and stromal components by releasing neurotransmitters such as norepinephrine (NE), creating a pro-tumor metabolic and immunosuppressive microenvironment. SNS signaling enhances glycolysis via upregulation of glucose transporter 1 (GLUT1) and glycolytic enzymes, and supports lipid metabolism through fatty acid synthesis and oxidation. In immune cells, SNS-driven metabolic shifts promote immunosuppressive phenotypes, particularly in T cells and macrophages. Concurrently, SNS signaling enhances glycolysis in endothelial cells, thereby facilitating angiogenesis within the TME. Together, these processes collectively sustain tumor growth, invasion, and resistance to therapy. Therapeutic strategies targeting SNS signaling, such as adrenergic receptors (ARs) blockers, show promise in disrupting these tumor-supportive networks. However, challenges such as the non-specific nature of SNS blockade and the complexity of TME interactions necessitate further research into ARs subtypes, tumor-specific metabolic vulnerabilities, and predictive biomarkers. This review highlights the therapeutic potential of targeting SNS signaling to reshape tumor metabolism and the microenvironment. By elucidating the metabolic impacts of its systemic and local arms, it provides a framework for integrating SNS-directed strategies with existing treatments to improve clinical outcomes.