EMBO Molecular Medicine (Mar 2024)

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor

  • Yuan Yang,
  • Zefei Li,
  • Yidong Wang,
  • Jiwei Gao,
  • Yangyang Meng,
  • Simeng Wang,
  • Xiaoyao Zhao,
  • Chengfang Tang,
  • Weiming Yang,
  • Yingjia Li,
  • Jie Bao,
  • Xinyu Fan,
  • Jing Tang,
  • Jingyu Yang,
  • Chunfu Wu,
  • Mingze Qin,
  • Lihui Wang

DOI
https://doi.org/10.1038/s44321-024-00051-z
Journal volume & issue
Vol. 16, no. 4
pp. 885 – 903

Abstract

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Abstract 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.

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