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.