Nicotinamide Riboside Restores NAD+ and Counters Tumor Hyperprogression: Preclinical Findings

Synopsis

Immune checkpoint blockade (ICB) therapy can sometimes cause tumors to grow faster, a problem called hyperprogressive disease (HPD). This study found that when immune cells release interferon-gamma (IFNγ) during treatment, it activates tumor pathways that disrupt a metabolic enzyme (PKM2) and sharply reduce NAD+ levels. With less NAD+, the SIRT1 enzyme becomes less active, allowing β-catenin to become over-acetylated and switch tumor cells into a faster-growing, stem-like state. To see if restoring NAD+ could stop this process, researchers treated melanoma cells with nicotinamide riboside (NR), an NAD+-boosting nutrient. NR reversed these harmful effects by reducing β-catenin acetylation, lowering β-catenin activity, and decreasing its cancer-promoting gene signals; NMN produced similar results. NR and NMN specifically blocked the β-catenin pathway without affecting other cancer pathways, showing that IFNγ drives tumor hyperprogression by lowering NAD+, and that boosting NAD+ with NR may help counteract this dangerous response.

Journal

Cancer Cell