Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.
Synopsis: The proposed interaction of NAMPT and PD-L1 and their dual targeting by LZFPN-90 were explored, raising the possibility that the pharmacological blockade of NAMPT and simultaneous immune checkpoint blockade represent a promising strategy for cancer therapy.The expression of PD-L1 and NAMPT is negatively correlated by epigenetic and glycolysis regulatory mechanisms.Pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65.Blocking PD-L1 induces NAMPT expression through a HIF-1-dependent glycolysis pathway.The PD-1/PD-L1 interaction and NAMPT activity are effectively inhibited by the dual NAMPT/PD-L1 targeting compound LZFPN-90.
The proposed interaction of NAMPT and PD-L1 and their dual targeting by LZFPN-90 were explored, raising the possibility that the pharmacological blockade of NAMPT and simultaneous immune checkpoint blockade represent a promising strategy for cancer therapy.