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

• Published in: EMBO molecular medicine 2024-04, Vol.16 (4), p.885-903
• Main Authors: Yang, Yuan, Li, Zefei, Wang, Yidong, Gao, Jiwei, Meng, Yangyang, Wang, Simeng, Zhao, Xiaoyao, Tang, Chengfang, Yang, Weiming, Li, Yingjia, Bao, Jie, Fan, Xinyu, Tang, Jing, Yang, Jingyu, Wu, Chunfu, Qin, Mingze, Wang, Lihui
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer; Co-targeting Therapy; EMBO03; EMBO21; Molecular Medicine; NAMPT/PD-L1; Tumor Immune Microenvironment
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-024-00051-z

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 NAMPT High PD-L1 Low 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 repr