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Updated: Aug 6, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

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SIRT7 orchestrates melanoma progression by simultaneously promoting cell survival and immune evasion via UPR

Xiuli Yi1, Huina Wang1, Yuqi Yang1

  • 1Department of Dermatology, Xijing Hospital, Fourth Military Medical University, No 127 of West Changle Road, Xi'an, Shaanxi, 710032, China.

Signal Transduction and Targeted Therapy
|March 15, 2023
PubMed

Insights

SIRT7 promotes melanoma growth and immune evasion by activating the unfolded protein response. Suppressing SIRT7 may enhance immunotherapy effectiveness against this lethal skin cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Melanoma remains a lethal skin cancer with suboptimal patient prognosis despite advances in therapy.
  • The tumor microenvironment presents significant stress to melanoma cells.
  • SIRT7, a NAD+-dependent deacetylase, maintains cell homeostasis, but its role in melanoma under stress is unclear.

Purpose of the Study:

  • To investigate the role of SIRT7 in melanoma progression and immune evasion under stressful conditions.
  • To elucidate the underlying molecular mechanisms by which SIRT7 influences melanoma cell survival and the tumor microenvironment.

Main Methods:

  • Assessed SIRT7 expression levels in sirtuins family under stress.
  • Utilized in vitro and in vivo models to evaluate the effects of SIRT7 deficiency on melanoma.
  • Investigated SIRT7's impact on the IRE1α-XBP1 axis, ERK signaling, and cytokine secretion.
  • Examined SIRT7's regulation of SMAD4 and TGF-β signaling.
  • Analyzed SIRT7's role in PD-L1 expression and anti-tumor immunity.
  • Evaluated combination therapy of SIRT7 suppression and anti-PD-1 blockade.

Main Results:

  • SIRT7 expression significantly increased under stress and was the highest among sirtuins.
  • SIRT7 deficiency led to increased tumor cell death under stress and suppressed melanoma growth in vivo.
  • SIRT7 activated the IRE1α-XBP1 pathway, enhancing pro-survival ERK signaling and tumor-promoting cytokines.
  • SIRT7 de-acetylated SMAD4, antagonizing TGF-β signaling and promoting IRE1α-XBP1 activation.
  • SIRT7 upregulation promoted PD-L1 expression, contributing to immune evasion.
  • Combined SIRT7 suppression and anti-PD-1 blockade showed synergistic therapeutic effects.

Conclusions:

  • SIRT7 drives melanoma progression by promoting cell survival and immune evasion through the unfolded protein response.
  • SIRT7 directly impacts key signaling pathways, including IRE1α-XBP1, ERK, and TGF-β.
  • SIRT7 inhibition represents a potential therapeutic strategy to overcome resistance and enhance melanoma immunotherapy.

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