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Updated: Nov 14, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Published on: June 7, 2019

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Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses

Fan Huang1,2, Christophe Gonçalves1, Margarita Bartish1,2

  • 1Lady Davis Institute, Jewish General Hospital, Montréal, Quebec, Canada.

The Journal of Clinical Investigation
|March 10, 2021
PubMed

Insights

Blocking the MNK1/2-eIF4E pathway inhibits melanoma cell plasticity and enhances anti-PD-1 immunotherapy response. This approach increases melanocytic antigens and T cell infiltration, offering a new strategy for melanoma treatment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Melanoma exhibits phenotype switching, contributing to immunotherapy resistance.
  • Mechanisms driving this plasticity and resistance are not fully understood.
  • Targeting tumor cell plasticity is a potential therapeutic strategy.

Purpose of the Study:

  • To investigate the role of the MNK1/2-eIF4E axis in melanoma phenotype switching.
  • To determine if blocking this axis sensitizes melanoma to anti-PD-1 immunotherapy.
  • To explore the therapeutic potential of dual blockade of MNK1/2-eIF4E and PD-1/PD-L1.

Main Methods:

  • Utilized melanoma mouse models.
  • Investigated the MNK1/2-eIF4E signaling pathway.
  • Assessed melanoma phenotype switching and immune microenvironment modulation.
  • Evaluated the efficacy of MNK1/2 inhibitors combined with anti-PD-1 therapy.

Main Results:

  • Blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching.
  • Deficiency in phospho-eIF4E led to increased melanocytic antigens in murine and patient melanomas.
  • Targeting this axis reprogrammed the immunosuppressive microenvironment, increasing CD8+ T cell infiltrates.
  • Dual blockade demonstrated efficacy across various melanoma models, increasing stem-like T cells.

Conclusions:

  • The MNK1/2-eIF4E axis is a critical regulator of melanoma phenotype switching.
  • Repressing phospho-eIF4E enhances melanoma antigen presentation and immune cell infiltration.
  • Dual blockade of MNK1/2-eIF4E and PD-1/PD-L1 shows promise for melanoma treatment.
  • Targeting melanoma plasticity offers a strategy to overcome immunotherapy resistance.
Keywords:
MelanomaOncology

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