A recent groundbreaking study published in Nature  unveils a novel mechanism by which lysosomal iron can trigger ferroptosis. This study unravels that ferroptosis, an iron-mediated cell death characterized by lipid oxidation, can be initiated in lysosomes. Ferroptosis has been gathering an increased interest in cancer research over the past years, and deciphering its underlying pathways are of utmost importance for the development of new anticancer strategies. This line of research offers promising avenues for the development of new cancer therapies. The research reported in Nature sheds light on the intricate relationship between iron metabolism within lysosomes and lipid oxidation, revealing potential molecular targets to selectively eliminate cancer cells resistant to conventional treatments, also called persister cancer cells.

Despite recent major advances in cancer care, some cancers, such as pancreatic cancer, triple negative breast cancer and lung cancer, have low survival rates upon diagnosis and subsequent standard-of-care treatments. Persister cancer cells and cancer cell plasticity can cause relapse and metastases and the latter account for the majority of cancer deaths. Metastatic cancers often spread into lung, liver, brain and bone, turning the disease from a local to a systemic one, which makes treatment challenging. There is an elevated amounts of iron in persister cancer cells. In these cells, iron is taken up preferentially by CD44-mediated endocytosis, where iron binds to hyaluronic acid and this glycan biopolymer is endocytosed together with the metal by CD44 and traffics via the endolysosomal route. Iron is required for the functioning of iron-dependent demethylases, which orchestrate gene expression required for the acquisition of distinct cell states, such as the persister prometastatic cancer cell state.

As described in this study, the authors have identified that persister cancer cells have elevated levels of iron in lysosomes, and that these cells are vulnerable to being therapeutically targeted with newly developed drugs. To exploit this mechanism, the authors designed a new molecule (called Fentomycin-1) consisting of two moieties with distinct properties. On the one hand, the molecule has a part that specifically targets lysosomes, and on the other hand it has a moiety that exploits the chemistry of iron. This molecule thus activates lysosomal iron, which generates radical oxygen species specifically in persister cancer cells, leading to lipid oxidation and subsequent cell death.

The authors obtained fresh human tumor samples from patient surgeries and conducted extensive biochemical and in vivo experimentation to verify their hypotheses. Employing state-of-the-art techniques, including NMR titration, cyclic voltammetry, and molecular modeling, the research team synthesized and characterized novel lysosomal iron chelators, to manipulate lysosomal iron chemistry. These small molecules enabled precision tracking and interference with intracellular iron pools, facilitating dissection of the role of lysosomal iron in oxidative cell damage. The authors show that they can specifically eradicate persister cancer cells in cell culture systems and in patient biopsies, making this a promising and viable strategy to develop medications against metastasis formation. Taken together, this work illuminates a novel and promising strategy for the development of next generation cancer treatments, with the aim to tackle metastatic spread, a still incurable phenomenon in most cases.