2. Academic Validation
  3. The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor

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

  • EMBO Mol Med. 2024 Apr;16(4):885-903. doi: 10.1038/s44321-024-00051-z.
Yuan Yang # 1 2,  Zefei Li # 3,  Yidong Wang 1 2,  Jiwei Gao 1 2,  Yangyang Meng 3,  Simeng Wang 1 2,  Xiaoyao Zhao 1 2,  Chengfang Tang 1 2,  Weiming Yang 1 2,  Yingjia Li 1 2,  Jie Bao 4,  Xinyu Fan 5,  Jing Tang 4,  Jingyu Yang 1 2,  Chunfu Wu 1 2,  Mingze Qin 6,  Lihui Wang 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.
  • 2 Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, PR China.
  • 4 Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland.
  • 5 Department of Pharmacy, Shengjing Hospital of China Medical University, 110004, Shenyang, PR China.
  • 6 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, PR China. qinmingze@syphu.edu.cn.
  • 7 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China. lhwang@syphu.edu.cn.
  • 8 Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, PR China. lhwang@syphu.edu.cn.
  • # Contributed equally.
PMID: 38448544 DOI: 10.1038/s44321-024-00051-z
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.

Keywords

Cancer; Co-targeting Therapy; NAMPT/PD-L1; Tumor Immune Microenvironment.

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