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For decades, scientists have known that a protein made by T cells and natural killer (NK) cells in the immune system, called perforin, can kill tumor cells by punching a hole in the cell wall and injecting proteases called granzymes, which kill the cell. Now, new work led by researchers at the University of Michigan Health Rogel Cancer Center found that tumor cells could be killed even when major granzymes were missing.

"If T cells and NK cells are the soldiers of the immune system, perforin is the weapon, and granzymes are the ammunition," said co-senior study author Weiping Zou, Charles B. de Nancrede professor of pathology, immunology, biology and surgery at U-M. "At least, that's what the classic understanding was."

Their new study, published in Cell, reveals that perforin is a cancer killer on its own, no major granzymes needed. They also found that a loss of perforin causes a catastrophic failure of antitumor immunity. The discoveries will likely have implications for understanding how cancers are killed by immune cells and could have ripple effects throughout the field of immunology.

"Our findings show, for the first time, that perforin can independently induce ferroptosis in tumor cells," said co-senior author Ilona Kryczek, a researcher at U-M.

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