Key points:
Metastatic melanoma cells that have spread to lymph nodes survive by relying on a protein called ferroptosis suppressor protein 1 (FSP1)—a finding that points to FSP1 inhibitors as a potentially effective treatment for cancer progression.
The study illuminates how metastasizing cancer cells can adapt to survive in lymph nodes, suggesting that treatments can be tailored to exploit cancer's unique weaknesses according to where it is located in the body.
The study also highlights new ways to understand cancerous cell death using in vivo models of cancer metastasis.
Boston, MA—Metastatic melanoma cells that have spread to lymph nodes survive by relying on a protein called ferroptosis suppressor protein 1 (FSP1)—a surprising metabolic dependency that could open the door to a new class of cancer treatments, according to a new study led by Harvard T.H. Chan School of Public Health. The researchers say the study not only highlights the therapeutic potential of drugs that inhibit FSP1, but also offers new ways to understand cancer and its vulnerabilities.
Ferroptosis is a form of cell death driven by excessive lipid oxidation in cell membranes. When this occurs, the cell's structural integrity collapses, leading to death. Cancer cells rely heavily on antioxidant proteins like FSP1 to prevent ferroptosis.
"Our study shows that melanoma cells in lymph nodes become dependent on FSP1 to survive, and that it is possible to decrease melanoma cell survival in lymph nodes with novel FSP1 inhibitors," said corresponding author Jessalyn Ubellacker, assistant professor of molecular metabolism. "These findings lay the foundation for potential new therapeutic strategies aimed at slowing cancer progression by targeting ferroptosis defense mechanisms."
The study will be published November 5, 2025, in Nature.
Ferroptosis has long been suggested as a strategy to kill cancer cells. Most research into understanding factors that drive ferroptosis resistance has focused on discoveries made in cells grown in plastic dishes (known as in vitro contexts). For this study, the researchers took a different approach, asking how cancer cells' environment in vivo (in a live organism) may change their mode of protection against ferroptosis. The researchers specifically investigated melanoma cells that had metastasized and moved into lymph nodes, using melanoma tumors in the lymph nodes of mice to do so. They then tested the efficacy of new FSP1 inhibitors directly in the tumors.
The study found that inside lymph nodes, FSP1 is a key line of defense against cell death. When the researchers delivered FSP1 inhibitors to the tumors, the tumors' growth was sharply reduced. In comparison, they tested this same drug on melanoma in vitro and saw little impact on cancer cell death.
The researchers noted that, in addition to pointing to the potential effectiveness of FSP1 inhibitors as a cancer treatment, the study helps to reframe how scientists think about ferroptosis in cancer—not as a single, uniform process, but as one that depends heavily on the tissue context.
"Metastatic disease, not the primary tumor, is what kills most cancer patients. Yet little is understood about how cancer cells adapt to survive in organs such as lymph nodes," said first author Mario Palma, postdoctoral research fellow in the Ubellacker Lab. "We discovered that niche features of the lymph node actively shape which antioxidant systems melanoma can use. That context-specific dependency had not yet been fully appreciated and suggests that, rather than trying to kill every tumor cell the same way, we can exploit the weaknesses that arise as cancer spreads."
In the same issue, Nature published a complementary study led by the Papagiannakopoulus Laboratory at New York University, showing that inhibiting FSP1 in lung cancer cells triggers ferroptosis and slows tumor growth. Together, the two studies strengthen the case for FSP1 as a promising target across multiple cancer types.
Article information
"Lymph node environment drives FSP1 targetability in metastasizing melanoma," Mario Palma, Milena Chaufan, Cort B. Breuer, Sebastian Müller, Marie Sabatier, Cameron S. Fraser, Krystina J. Szylo, Mahsa Yavari, Alanis Carmona, Mayher Kaur, Luiza Martins Nascentes Melo, Feyza Cansiz, June Monge-Lorenzo, Midori Flores, Eikan Mishima, Toshitaka Nakamura, Bettina Proneth, Marcos Labrado, Yanshan Liang, Nicole Cayting, Lan Zheng, Tatiana Cañeque, Ludovic Colombeau, Adam Wahida, José Pedro Friedmann Angeli, Alpaslan Tasdogan, Sheng Hui, Raphaël Rodriguez, Marcus Conrad, Nathan E. Reticker-Flynn, Jessalyn M. Ubellacker, Nature, November 5, 2025, doi: 10.1038/s41586-025-09709-1
The study was supported by the Ludwig Center at Harvard, the Melanoma Research Program Department of Defense Team Science Award, the Melanoma Research Foundation Young Career Investigators Award, the National Cancer Institute (grant R01CA282202), the National Institutes of Health (grant DP2 AI177915), the METAvivor Early Career Investigator Award, and an Arc Institute Fellowship.
The new FSP1 inhibitors used in the study were developed in Dr. Marcus Conrad's laboratory at Helmholtz Munich and Dr. James Olzmann's Laboratory at University of California, Berkeley.
Conrad, Proneth, Nakamura, Rodriguez, Müller, Cañeque, and Colombeau are listed as inventors on some of the compounds described in the study, and Conrad and Proneth are co-founders and shareholders of ROSCUE Therapeutics GmbH.
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