Lymph node environment drives FSP1 targetability in metastasizing melanoma
Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers<sup>1</sup>. 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 metastasis<sup>2</sup>. 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.
Authors
- Luiza Martins Nascentes Melo (ORCID: https://orcid.org/0000-0002-5980-5220)
- Raphaël Rodriguez (ORCID: https://orcid.org/0000-0001-7668-446X)
- Jessalyn M. Ubellacker (ORCID: https://orcid.org/0000-0002-7855-9125)
- Cort B. Breuer (ORCID: https://orcid.org/0009-0009-2594-3754)
- Tatiana Cañeque (ORCID: https://orcid.org/0000-0002-1110-0643)
- Marcus Conrad (ORCID: https://orcid.org/0000-0003-1140-5612)
- Bettina Proneth (ORCID: https://orcid.org/0000-0002-4119-9437)
- Alanis Carmona
- Yanshan Liang (ORCID: https://orcid.org/0000-0002-5783-1636)
- Alpaslan Tasdogan (ORCID: https://orcid.org/0000-0003-2543-852X)
- Sebastian Müller (ORCID: https://orcid.org/0000-0002-3423-5364)
- Feyza Cansiz (ORCID: https://orcid.org/0009-0006-6526-990X)
- Mayher Kaur (ORCID: https://orcid.org/0009-0007-2097-4063)
- Toshitaka Nakamura (ORCID: https://orcid.org/0000-0002-4248-2058)
- Ludovic Colombeau (ORCID: https://orcid.org/0000-0001-5823-2603)
- José Pedro Friedmann Angeli (ORCID: https://orcid.org/0000-0001-7706-1379)
- Eikan Mishima (ORCID: https://orcid.org/0000-0002-3706-2745)
- Mahsa Yavari (ORCID: https://orcid.org/0000-0002-5906-7635)
- Adam Wahida (ORCID: https://orcid.org/0000-0002-8856-8834)
- Marie Sabatier (ORCID: https://orcid.org/0000-0001-7673-4842)
- Krystina J. Szylo (ORCID: https://orcid.org/0009-0007-0743-4812)
- Nathan E. Reticker-Flynn (ORCID: https://orcid.org/0000-0002-9963-039X)
- Cameron Fraser (ORCID: https://orcid.org/0000-0002-8180-5913)
- Hui Sheng (ORCID: https://orcid.org/0000-0002-2040-8842)
- Lan Zheng (ORCID: https://orcid.org/0000-0003-2738-9063)
- Mario Palma (ORCID: https://orcid.org/0009-0007-9456-2096)
- Midori Flores
- Marcos Labrado (ORCID: https://orcid.org/0009-0008-3981-2651)
- Nicole Cayting
- June Monge-Lorenzo (ORCID: https://orcid.org/0009-0007-8943-759X)
- Milena Chaufan
Institutions
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Inserm (FR)
- University of Würzburg (DE)
- Université Paris Sciences et Lettres (FR)
- Vlaams Instituut voor Biotechnologie (BE)
- Ghent University (BE)
- Essen University Hospital (DE)
- Dana-Farber/Harvard Cancer Center (US)
- VIB-UGent Center for Inflammation Research (BE)
- Target (Germany) (DE)
- Technical University of Munich (DE)
- Stanford University (US)
Publication Details
- Journal
- Nature
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1038/s41586-025-09709-1
- Citations
- 18
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 27.33