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NAD+ Metabolism Reprogramming Drives SIRT1-Dependent Deacetylation Inducing PD-L1 Nuclear Localization in Cervical

Xinyi Lu1,2, Pingping Jin1, Qianyun Tang1

  • 1Affiliated Women's Hospital of Jiangnan University, Jiangnan University, Jiangsu, 214002, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 24, 2025
PubMed

Insights

A novel metabolic pathway involving NAMPT and SIRT1 regulates PD-L1 expression in cervical cancer, potentially overcoming immunotherapy resistance. Targeting this axis may improve treatment outcomes for patients.

Area of Science:

  • Oncology
  • Immunology
  • Metabolism

Background:

  • Cervical cancer (CC) poses a significant health risk to women.
  • Immunotherapy targeting the programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) axis shows promise but faces resistance in many patients.
  • Understanding resistance mechanisms is crucial for improving CC treatment.

Purpose of the Study:

  • To uncover the mechanisms underlying immunotherapy resistance in cervical cancer.
  • To identify novel metabolic pathways regulating PD-L1 expression and localization.
  • To explore the potential of targeting these pathways for enhanced therapeutic responses.

Main Methods:

  • Investigated the role of the nicotinamide adenine dinucleotide (NAD+) salvage pathway, specifically nicotinamide phosphoribosyltransferase (NAMPT) and Sirtuin 1 (SIRT1).
  • Utilized acetyl-proteomic analysis to identify regulators of PD-L1 expression.
  • Examined the epigenetic regulation of PD-L1 by metabolic pathways.

Main Results:

  • Identified a novel metabolic axis involving NAMPT and SIRT1 that regulates PD-L1 expression and nuclear localization in CC.
  • Demonstrated that SIRT1 deacetylates histone H3 at lysines 27, influencing PD-L1 subcellular distribution.
  • Revealed that PD-L1 overexpression is controlled by both transcriptional and post-transcriptional processes.

Conclusions:

  • The NAMPT/SIRT1 metabolic axis is a key factor in cervical cancer immunotherapy resistance.
  • Targeting the NAMPT/SIRT1 axis offers a potential strategy to enhance therapeutic responses in CC.
  • This study provides new insights into the epigenetic control of immune checkpoint proteins by metabolic pathways.
Keywords:
NAD+ metabolismPD‐L1, SIRT1acetyl‐proteomicscervical cancerimmunotherapy resistance

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