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 γ (IFNγ)-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 α-ketoglutarate (α-KG). IFNγ-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 antibody provides a promising therapeutic strategy for immunotherapy-resistant tumors.