Cancer Stem Cells have high amounts of lysosomal iron

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.

A chimera molecule linking lysosomal targeting an iron activation

By taking advantage of a small molecule scaffold that is fluorescent and targets specifically lysosomes, the natural product Marmycin A, linked to a moiety that activates lysosomal iron, the novel small molecule Fentomycin-1 can specifically target and activate lysosomal iron. This molecule can kill specifically cancer stem cells in vitro and from fresh human tumour biopsies, by targeting these cells rich in lysosomal iron.

A family of small molecules

Other moieties that target lipid membranes have been employed instead of marmycin A, such as cholesterol, that anchoor to the membrane and are taken up into lysosomes by endocytosis (see scheme below).

Taken together, this new family of small lipid degraders has promise for the development of new anti-cancer drugs, specifically targeting cells responsible for relapse and metastasis formation.

Original publication: Nature, 2025, Activation of lysosomal iron triggers ferroptosis in cancer