Abstract
Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation. Some therapy-resistant cancer cells remain vulnerable to this process, creating interest in disrupting the defenses that prevent membrane oxidation. This review critically examines how lipoprotein-derived α-tocopherol contributes to ferroptosis resistance and how its protective effects can be distinguished from lipid remodeling and intracellular antioxidant compensation. We integrate evidence on circulating antioxidant carriers, glycosaminoglycan-dependent uptake, and scavenger receptor class B type 1-mediated delivery, including regulation by mechanistic target of rapamycin complex 1. We compare the experimental support and limitations of these mechanisms and consider how tissue environments alter antioxidant availability and defense requirements. The available evidence supports extracellular α-tocopherol acquisition as an additional layer of ferroptosis protection in selected experimental cancer models; its prevalence and therapeutic importance in human tumors remain unresolved. Establishing dependence requires cargo-specific measurements, controlled uptake perturbations, membrane lipid analysis, and confirmation of ferroptotic death. Therapeutic targeting will require functional biomarkers and evidence that restricting antioxidant supply compromises tumor survival within a tolerable therapeutic window.