Friedmann Angeli

Melanoma is characterized by high degrees of phenotypic heterogeneity originating from the impact of the microenvironment on epigenetically plastic cancer cells, with different phenotypes exhibiting different sensitivities to both targeted and immunotherapies. For example, MITFLow invasive melanoma cells are more resistant to BRAFi but exhibit an increased sensitivity to ferroptosis. What determines sensitivity to ferroptosis is not well understood.

Ferroptosis is a unique form of cell death that is biochemically and morphologically distinct from other types of cell death such as apoptosis, necrosis, autophagy, and pyroptosis (1–3). Ferroptosis is known to be caused by lipid peroxidation and intracellular iron-mediated membrane oxidative damage induced by cystine depletion (4–6). Solute carrier family 7 member 11 (SLC7A11) is a subunit of the cystine/glutamate antiporter system Xc− and is the major transporter of extracellular cystine (7–9).

Metabolic reprogramming is a pivotal hallmark of cancer that contributes to therapy resistance (1). Cancer cells possess the remarkable ability to modify their metabolism, enabling them to regulate Reactive Oxygen Species (ROS) levels. Maintaining ROS at moderate levels facilitates cell survival and proliferation. Understanding the intricacies of cancer redox metabolism is crucial for identifying specific targets that can improve therapy efficacy.