Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity
Menée à l'aide de lignées cellulaires, d'organoïdes de carcinome colorectal, de modèles murins et de données portant sur des patients atteints d'un mélanome, cette étude met en évidence un mécanisme par lequel la perforine favorise, sans l'aide des granzymes, la ferroptose et l'immunité antitumorale via la formation de pores, l'endocytose du récepteur de la transferrine, le développement de contacts endosomaux-mitochondriaux, l'accumulation de fer dans les mitochondries et le dysfonctionnement de ces dernières
Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
Cell , article en libre accès, 2026