Induction of Cell Death by Combined Treatment with Photosensitizer‐Chitosan Nanoparticles and the Ferroptosis Inducer RSL3 in Breast Cancer Cell Lines

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Breast cancer, a prevalent malignancy worldwide, includes the triple‐negative subtype (TNBC) characterized by poor treatment outcomes. TNBC has been shown to be sensitive to ferroptotic cell death, an iron‐dependent cell death mechanism involving reactive oxygen species (ROS) and lipid peroxidation. Herein, biodegradable tetraphenylchlorin‐conjugated chitosan nanoparticles (TPC‐CS NPs) in combination with the free ferroptosis inducer RSL3 is used in MCF7 (hormone receptor‐positive, epithelial) and MDA‐MB‐231 (hormone receptor‐negative, mesenchymal‐like) breast cancer cell lines. The results show that RSL3 treatment has no cytotoxic effect in MCF7 and there is no enhanced sensitivity when combined with TPC‐CS NPs, while the combination sensitizes MDA‐MB‐231 cells. Western blot analysis reveals that the combined treatment decreases and differently affects GPX4 levels and the ratio between the two GPX isoforms in the two cell lines. In MDA‐MB‐231 cells, the combined treatment shows enhanced effects on lipid peroxidation, mitochondrial potential, and basal and maximal respiration, as compared to single treatments. Finally, ferroptosis expression signatures distinguish breast cancer cell lines with an increasing score in mesenchymal‐like cells. Moreover, the signatures correlate with breast cancer subtypes, exhibiting the highest scores in subtypes rich in mesenchymal‐like cells, particularly basal‐like and claudin‐low tumors, suggesting their susceptibility to ferroptosis induction.