Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.

Perforin (Prf1) directly induces tumoral ferroptosis by driving endosomal-mitochondrial contacts that cause mitochondrial iron accumulation and mitochondrial dysfunction.

• Why it matters: Cytotoxic CD8+ T cells and natural killer cells rely on Prf1, but a Gzm-independent mechanism linking Prf1 to iron-dependent tumor cell death was unclear.
• What they did: The study shows Prf1 pore formation triggers transferrin receptor endocytosis, increases iron uptake, promotes endosomal-mitochondrial contacts, and leads to ferroptosis in tumor cells.
• The result: In murine tumor models, dietary iron supplementation suppresses tumor progression in a Prf1-dependent manner, and higher Prf1 expression correlates with improved survival and better immune checkpoint blockade response in patients with cancer.

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