Why Is the Tumor Microenvironment Disordered by NADH/NAD+ Imbalance and How Can We Intervene?

NADH and NAD + are crucial redox cofactors in biological systems, participating in the mitochondrial respiratory chain and playing significant roles in various metabolic processes. Increasing evidence indicates that changes in the NADH/NAD + ratio play a critical role in tumor biology. In this review, we focus on the physiological functions of the NADH/NAD + redox couple and its core role in tumor initiation and progression, and we further examine the key mechanisms of NADH/NAD + ratio imbalance during tumor development, including metabolic reprogramming and interactions with the immune microenvironment. Finally, we summarize the emerging therapeutic strategies targeting the NADH/NAD + ratio from the perspective of regulating NADH and NAD + synthesis, shuttling, and metabolic microenvironment. These insights provide a theoretical framework and promising directions for the development of novel NADH/NAD + -targeted anti-tumor therapies.