Cancer cells often suppress ferroptosis—an iron-fueled mechanism of cell death driven by the rampant oxidation of membrane lipids—by expressing high levels of antioxidant proteins. Researchers led by Ludwig Harvard’s Mario Palma and Jessalyn Ubellacker reported in a November issue of Nature that melanoma cells that metastasize to the lymph nodes become highly dependent on one such protein known as ferroptosis suppressor protein 1 (FSP1). They show that FSP1 inhibitors significantly curtailed tumor growth in a mouse model of melanoma that favors lymph node metastases. Notably, FSP1-dependency is an adaptation of melanomas spreading through the lymph nodes; subcutaneous melanoma tumors are not susceptible to FSP1 inhibition. Jessalyn and her colleagues showed that a metabolic shift likely leads to FSP1 dependency. Melanoma cells traveling through the bloodstream rely on another protein, GPX4, to resist ferroptosis. Those in lymph nodes lose that dependency. GPX4 is lost to ubiquitination and degradation by proteasomes in hypoxic conditions comparable to those found in the microenvironment of the lymphatic niche, leaving the cells dependent on FSP1 to guard against ferroptosis. Aside from identifying a potential drug target for metastatic melanoma, the study illustrates how important it is to examine ferroptosis and other processes targeted for cancer therapy in the context of their natural tissue microenvironment.
Lymph node environment drives FSP1 targetability in metastasizing melanoma
Nature, 2025 November 5