Unsaturated\nFatty Acid Liposomes Selectively Regulate\nGlutathione Peroxidase 4 to Exacerbate Lipid Peroxidation as an Adaptable\nLiposome Platform for Anti-Tumor Therapy

Regulating\nnon-apoptotic cell death of cancer cells provides\na\npromising strategy to overcome apoptosis resistance during cancer\ntreatment. Lipids are essential components to exacerbate several non-apoptotic\ncell death pathways. In the present study, unsaturated fatty acid\n(UFA) liposomes prepared with linoleic acid, oleic acid, or α-linolenic\nacid have the potential to affect lipid metabolism. Notably, UFA liposomes\nmarkedly increased cellular reactive oxygen species (ROS) and down-regulated\nthe expression of glutathione peroxidase 4 (GPX4) in tumor cells,\nresulting in lipid peroxidation, which in turn caused rapid membrane\nrupture and induced non-apoptotic cell death of tumor cells. Concomitantly,\nUFA liposomes induced ROS-mediated tumor-associated macrophages toward\na tumoricidal phenotype to reverse the immunosuppressive tumor microenvironment.\nConsequently, UFA liposomes substantially inhibited tumor growth in\na melanoma model by promoting lipid peroxidation, inducing non-apoptotic\ncell death of tumor cells, and increasing infiltration of anti-tumor\nimmune cells at tumor sites. Therefore, UFA liposomes regulate GXP4\nto exacerbate lipid peroxidation and provide a versatile liposome\nplatform for enhancing anti-tumor therapy which could be readily extended\nto the delivery of anticancer agents.