Palma Mario, Chaufan Milena, Breuer Cort B, Müller Sebastian, Sabatier Marie, Fraser Cameron S, Szylo Krystina J, Yavari Mahsa, Carmona Alanis, Kaur Mayher, Melo Luiza Martins Nascentes, Cansiz Feyza, Monge-Lorenzo June, Flores Midori, Mishima Eikan, Nakamura Toshitaka, Proneth Bettina, Labrado Marcos, Liang Yanshan, Cayting Nicole, Zheng Lan, Cañeque Tatiana, Colombeau Ludovic, Wahida Adam, Friedmann Angeli José Pedro, Tasdogan Alpaslan, Hui Sheng, Rodriguez Raphaël, Conrad Marcus, Reticker-Flynn Nathan E, Ubellacker Jessalyn M
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Otolaryngology-Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2026 Jan;649(8096):477-486. doi: 10.1038/s41586-025-09709-1. Epub 2025 Nov 5.
Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers. 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. 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.
铁死亡已成为消除治疗抵抗性和转移性癌症的一个可操作靶点。然而，哪些铁死亡监测系统可能为利用癌症中的氧化还原适应不良提供一个治疗窗口仍不清楚。在黑色素瘤中，谷胱甘肽过氧化物酶4（GPX4）在血行转移过程中阻碍铁死亡，但在淋巴转移过程中并非必需。在此，我们使用一个选择用于淋巴结转移的转移性小鼠黑色素瘤模型，结果表明，相对于其亲代细胞，淋巴结来源的转移性细胞表现出谷氨酸-半胱氨酸连接酶（GCLC）的表达显著降低以及谷胱甘肽（GSH）水平降低。这种代谢转变发生在低氧的淋巴微环境中。在类似的低氧条件下，GPX4会发生泛素化和蛋白酶体降解。作为响应，淋巴结转移性细胞对铁死亡抑制蛋白1（FSP1）的依赖性增加，FSP1定位于核周溶酶体。这些发现揭示了对GPX4轴依赖性的降低使黑色素瘤细胞转向对FSP1的依赖性。值得注意的是，用选择性FSP1抑制剂（viFSP1和FSEN1）进行瘤内单一疗法可有效抑制淋巴结中的黑色素瘤生长，但对皮下肿瘤无效，这强调了对FSP1的微环境特异性依赖性。因此，靶向淋巴结中的FSP1在阻断黑色素瘤进展方面具有强大潜力。
