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

Prf1 directly induces tumoral ferroptosis by driving endosomal-mitochondrial contacts that cause mitochondrial iron accumulation and dysfunction, in a Gzm-independent manner.

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