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Background <p>Metastatic cutaneous melanoma (MCM) is primarily treated with BRAF/MEK inhibitors and immune checkpoint inhibitors (ICIs), but the long-term efficacy of these therapies is often limited by acquired resistance. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, is frequently upregulated in MCM, supporting metabolic rewiring and targeted therapy resistance.</p> <p>Interferon-γ (IFN-γ) signaling plays a central role in melanoma biology, exerting both antitumor and immunoregulatory effects, linked with the onset of therapeutic resistance. Emerging evidence suggests that metabolic pathways may critically modulate IFN-γ responses; however, the functional interplay between NAD/NAMPT metabolism and IFN-γ signaling in melanoma cells remains poorly defined.</p> Methods <p>We integrated transcriptomic, bioinformatic, biochemical, and functional approaches in human and murine melanoma cell lines, together with analyses of TCGA datasets and a tissue microarray (TMA) cohort. Mechanistic studies included pharmacological and genetic perturbation of Bromodomain and Extra-Terminal motif (BET) epigenetic factor BRD4, Interferon Regulatory Factor 1 (IRF1), and NAMPT, chromatin immunoprecipitation (ChIP) assays, and metabolic analyses. Tumor-T cell co-culture systems were used to assess the impact of melanoma-cell NAMPT modulation on T-cell behavior.</p> Results <p>IFN-γ induced NAMPT expression through a BRD4/IRF1-dependent transcriptional program. In turn, NAMPT activity was required to sustain IFN-γ signaling, as its inhibition impaired STAT1 activation and downstream transcriptional responses. Mechanistically, NAMPT-dependent NAD metabolism supported mitochondrial complex I activity and oxidative metabolism and was required for efficient BRD4 recruitment to IFN-responsive promoters, including CD274/PD-L1 and NAMPT itself. Across melanoma datasets and patient samples, NAMPT expression correlated with IFN-γ–responsive genes, including PD-L1. Functionally, modulation of NAMPT in melanoma cells influenced T-cell cytotoxicity and migration in co-culture systems.</p> Conclusions <p>Overall, these findings identify NAMPT as a key metabolic component of the IFN-γ response network in melanoma cells, establishing a feed-forward regulatory circuit linking cytokine signaling, chromatin regulation, and mitochondrial metabolism. This work provides a framework to investigate how metabolic control of IFN-γ signaling shapes tumor-immune interactions.</p>

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Bi-directional regulation between NAD/NAMPT and IFN-γ/PD-L1 axes via BRD4/IRF1 and mitochondrial respiration in metastatic cutaneous melanoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Irene Fiorilla,
  • Beatrice Ghezzi,
  • Alessia Ponzano,
  • Enrico Moiso,
  • Federica Riccardo,
  • Nicoletta Tommasi,
  • Lidia Avalle,
  • Giovanna Carrà,
  • Filippo Ugolini,
  • Edoardo Calussi,
  • Alberto Maria Todesco,
  • Sabrina Digiovanni,
  • Filippo Casone,
  • Giulia Rizza,
  • Luca Ponzone,
  • Anna Szumera-Ciećkiewicz,
  • Maria Cavaletto,
  • Paolo Ettore Porporato,
  • Laura Conti,
  • Chiara Riganti,
  • Daniela Massi,
  • Enzo Calautti,
  • Valentina Audrito

摘要

Background

Metastatic cutaneous melanoma (MCM) is primarily treated with BRAF/MEK inhibitors and immune checkpoint inhibitors (ICIs), but the long-term efficacy of these therapies is often limited by acquired resistance. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, is frequently upregulated in MCM, supporting metabolic rewiring and targeted therapy resistance.

Interferon-γ (IFN-γ) signaling plays a central role in melanoma biology, exerting both antitumor and immunoregulatory effects, linked with the onset of therapeutic resistance. Emerging evidence suggests that metabolic pathways may critically modulate IFN-γ responses; however, the functional interplay between NAD/NAMPT metabolism and IFN-γ signaling in melanoma cells remains poorly defined.

Methods

We integrated transcriptomic, bioinformatic, biochemical, and functional approaches in human and murine melanoma cell lines, together with analyses of TCGA datasets and a tissue microarray (TMA) cohort. Mechanistic studies included pharmacological and genetic perturbation of Bromodomain and Extra-Terminal motif (BET) epigenetic factor BRD4, Interferon Regulatory Factor 1 (IRF1), and NAMPT, chromatin immunoprecipitation (ChIP) assays, and metabolic analyses. Tumor-T cell co-culture systems were used to assess the impact of melanoma-cell NAMPT modulation on T-cell behavior.

Results

IFN-γ induced NAMPT expression through a BRD4/IRF1-dependent transcriptional program. In turn, NAMPT activity was required to sustain IFN-γ signaling, as its inhibition impaired STAT1 activation and downstream transcriptional responses. Mechanistically, NAMPT-dependent NAD metabolism supported mitochondrial complex I activity and oxidative metabolism and was required for efficient BRD4 recruitment to IFN-responsive promoters, including CD274/PD-L1 and NAMPT itself. Across melanoma datasets and patient samples, NAMPT expression correlated with IFN-γ–responsive genes, including PD-L1. Functionally, modulation of NAMPT in melanoma cells influenced T-cell cytotoxicity and migration in co-culture systems.

Conclusions

Overall, these findings identify NAMPT as a key metabolic component of the IFN-γ response network in melanoma cells, establishing a feed-forward regulatory circuit linking cytokine signaling, chromatin regulation, and mitochondrial metabolism. This work provides a framework to investigate how metabolic control of IFN-γ signaling shapes tumor-immune interactions.