NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion.

NAD(+) metabolism is implicated in aging and cancer However, its role in immune checkpoint regulation and immune evasion remains unclear. Here, we find nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD(+) biogenesis, drives interferon gamma (IFN gamma)-induced PD-L1 expression in multiple types of tumors and governs tumor immune evasion in a CD8(+) T cell-dependent manner. Mechanistically, NAD(+) metabolism maintains activity and expression of methylcytosine dioxygenase Tet1 via alpha-ketoglutarate (alpha-KG). IFN gamma-activated Stat1 facilitates Tet1 binding to Irf1 to regulate Irf1 demethylation, leading to downstream PD-L1 expression on tumors. Importantly, high NAMPT-expressing tumors are more sensitive to anti-PD-L1 treatment and NAD(+) augmentation enhances the efficacy of anti-PD-L1 antibody in immunotherapy-resistant tumors. Collectively, these data delineate an NAD(+) metabolism-dependent epigenetic mechanism contributing to tumor immune evasion, and NAD(+) replenishment combined with PD-(L)1 anti-body provides a promising therapeutic strategy for immunotherapy-resistant tumors.