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S-nitrosylation of IRF7 induced by NOS1 expression in melanoma suppresses anti-tumor immunity

Yuxin Dai1, Sisi Zeng2,3,4, Keyi Li1

  • 1Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, China.

Cell Death & Disease
|January 14, 2026
PubMed

Insights

Nitric oxide synthase 1 (NOS1) in melanoma promotes tumor growth by inhibiting type I interferon signaling via IRF7 modification. Targeting NOS1 may overcome resistance to immune checkpoint blockade therapy, especially in immune-cold tumors.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Endogenous nitric oxide (NO) produced by nitric oxide synthases (NOSs) is immunosuppressive in the tumor microenvironment.
  • In melanoma, increased NOS1 expression correlates with immune escape by inhibiting type I interferon (IFN) signaling.
  • The precise immune regulatory mechanisms and therapeutic implications of NOS1 in melanoma are not fully understood.

Purpose of the Study:

  • To elucidate the immune regulatory role and molecular mechanisms of NOS1 in melanoma.
  • To investigate the impact of NOS1 on anti-tumor immunity and immune checkpoint blockade (ICB) therapy.
  • To explore NOS1 as a potential therapeutic target in melanoma.

Main Methods:

  • Investigated NOS1-mediated IRF7 modification (S-nitrosylation) in mouse melanoma models.
  • Assessed the effects of IRF7 S-nitrosylation on IFNβ transcription and type I IFN response initiation.
  • Analyzed the impact of NOS1/IRF7 signaling on CD8+ T cell infiltration, antigen presentation, and dendritic cell maturation.
  • Correlated NOS1 expression with patient survival and ICB therapy response in human melanoma cohorts.

Main Results:

  • NOS1 induces IRF7 S-nitrosylation at C481 (human), inhibiting IFNβ transcription and type I IFN responses in melanoma cells.
  • IRF7 S-nitrosylation reduces CD8+ T cell infiltration and activation by impairing antigen presentation and dendritic cell maturation.
  • High NOS1 expression is linked to poor prognosis and resistance to ICB therapy in melanoma patients with low immune infiltration.
  • NOS1 expression in melanoma is associated with disordered type I IFN signaling due to IRF7 S-nitrosylation.

Conclusions:

  • NOS1-driven IRF7 S-nitrosylation disrupts innate immune signaling in melanoma, promoting tumor growth and immune evasion.
  • Targeting NOS1 signaling represents a potential strategy to enhance anti-tumor immunity and overcome resistance to ICB, particularly in immune-cold melanoma.
  • NOS1 serves as a biomarker for poor prognosis and therapeutic resistance in melanoma.

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