Differential effects of N‐TiO2 nanoparticle and its photo‐activated form on autophagy and necroptosis in human melanoma A375 cells

Abstract The manipulation of autophagy provides a new opportunity for highly effective anticancer therapies. Recently, we showed that photodynamic therapy (PDT) with nitrogen‐doped titanium dioxide (N‐TiO 2 ) nanoparticles (NPs) could promote the reactive oxygen species (ROS)‐dependent autophagy in leukemia cells. However, the differential autophagic effects of N‐TiO 2 NPs in the dark and light conditions and the potential of N‐TiO 2‐ based PDT for the treatment of melanoma cells remain unknown. Here we show that depending on the visible‐light condition, the autophagic response of human melanoma A375 cells to N‐TiO 2 NPs switches between two different statuses (ie., flux or blockade) with the opposite outcomes (ie., survival or death). Mechanistically, low doses of N‐TiO 2 NPs (1‐100 µg/ml) stimulate a nontoxic autophagy flux response in A375 cells, whereas their photo‐activation leads to the impairment of the autophagosome‐lysosome fusion, the blockade of autophagy flux and consequently the induction of RIPK1‐mediated necroptosis via ROS production. These results confirm that photo‐controllable autophagic effects of N‐TiO 2 NPs can be utilized for the treatment of cancer, particularly melanoma.