2. Academic Validation
  3. Lymph node environment drives FSP1 targetability in metastasizing melanoma

Lymph node environment drives FSP1 targetability in metastasizing melanoma

  • Nature. 2025 Nov 5. doi: 10.1038/s41586-025-09709-1.
Mario Palma 1,  Milena Chaufan 1,  Cort B Breuer 2 3,  Sebastian Müller 4,  Marie Sabatier 1,  Cameron S Fraser 1,  Krystina J Szylo 1,  Mahsa Yavari 1,  Alanis Carmona 1,  Mayher Kaur 1,  Luiza Martins Nascentes Melo 1 5,  Feyza Cansiz 5,  June Monge-Lorenzo 1,  Midori Flores 1,  Eikan Mishima 6,  Toshitaka Nakamura 6,  Bettina Proneth 6,  Marcos Labrado 2 3,  Yanshan Liang 1,  Nicole Cayting 1,  Lan Zheng 2,  Tatiana Cañeque 4,  Ludovic Colombeau 4,  Adam Wahida 1 6 7 8,  José Pedro Friedmann Angeli 9,  Alpaslan Tasdogan 5,  Sheng Hui 1,  Raphaël Rodriguez 4,  Marcus Conrad 6 10,  Nathan E Reticker-Flynn 2 11,  Jessalyn M Ubellacker 12 13
Affiliations

Affiliations

  • 1 Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 2 Department of Otolaryngology-Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Program in Immunology, Stanford University, Stanford, CA, USA.
  • 4 Institut Curie, CNRS, INSERM, PSL Research University, Paris, France.
  • 5 Department of Dermatology, University Hospital Essen & German Cancer Consortium (DKTK), Essen, Germany.
  • 6 Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, Helmholtz Munich, Neuherberg, Germany.
  • 7 Molecular Signaling and Cell Death Unit, VIB-UGent Center for Inflammation Research, Flanders Institute for Biotechnology, Ghent, Belgium.
  • 8 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 9 Rudolf Virchow Center for Integrative and Translational Bioimaging, Chair of Translational Cell Biology, University of Würzburg, Würzburg, Germany.
  • 10 Translational Redox Biology, Technical University of Munich (TUM), TUM Natural School of Sciences, Garching, Germany.
  • 11 Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 12 Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [email protected].
  • 13 Ludwig Center at Harvard, Boston, MA, USA. [email protected].
PMID: 41193799 DOI: 10.1038/s41586-025-09709-1
Abstract

Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which Ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in Cancer remains unclear. In melanoma, Glutathione Peroxidase 4 (GPX4) impedes Ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate-cysteine Ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on Ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.

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