Related Experiment Video

Updated: Mar 24, 2026

Exploring the Arginine Methylome by Nuclear Magnetic Resonance Spectroscopy
07:02

Exploring the Arginine Methylome by Nuclear Magnetic Resonance Spectroscopy

Published on: December 16, 2021

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MYC-ATF4-ASS1 axis governs intracellular arginine synthesis and dictates the immune microenvironment in melanoma

Haiwei Mou1, Veronika Yakovishina1, Yeqing Chen1

  • 1Melanoma Research Center, Molecular and Cellular Biology Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104.

Biorxiv : the Preprint Server for Biology
|March 23, 2026
PubMed

Insights

MYC-ATF4-ASS1 signaling controls melanoma

Area of Science:

  • Oncology
  • Cancer Immunology
  • Molecular Biology

Background:

  • Drug resistance in cancer limits targeted and immunotherapy efficacy.
  • Arginine starvation is a potential strategy against recurrent tumors, but underlying mechanisms and immune modulation are unclear.

Purpose of the Study:

  • To identify key molecules in arginine metabolism and their role in melanoma's immune response.
  • To investigate the MYC-ATF4-ASS1 pathway's function in melanoma cell arginine synthesis and immune modulation.

Main Methods:

  • Utilized ATF4 knockout and Argininosuccinate Synthetase 1 (ASS1) knockout in melanoma cells.
  • Employed a combination therapy of BRAF/MEK inhibitors and an arginine depletor in immunocompromised mice.
  • Conducted experiments in syngeneic mouse models with knockout melanomas.
  • Performed single-cell transcriptomics to analyze the tumor microenvironment.

Main Results:

  • ATF4 knockout mirrored ASS1 knockout, increasing sensitivity to arginine depletors like ADI-PEG20.
  • Combined BRAF/MEK inhibitors and arginine depletion showed therapeutic effects in mice.
  • Atf4 and Ass1 knockout melanomas displayed increased CD8+ T cell infiltration and reduced tumor growth.
  • Single-cell transcriptomics revealed macrophage reprogramming due to endogenous arginine blockade.

Conclusions:

  • The MYC-ATF4-ASS1 axis regulates melanoma's arginine synthesis and vulnerability.
  • This pathway significantly shapes the tumor immune microenvironment, influencing T cell infiltration and macrophage activity.
  • Targeting this axis offers a novel strategy for overcoming drug resistance and enhancing anti-tumor immunity.

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