A TNF-producing neutrophil subset drives age-dependent hepatotoxicity

The mechanisms by which aging contributes to the detrimental effect of cancer therapy remain poorly understood. Herein we show that while a synthetic dsRNA (polyIC) effectively suppresses liver tumors in young mice, it induces lethal liver necrosis in aged mice. Single-cell and functional analyses unearthed a CD14⁺ neutrophil subset featured by robust TNFalpha induction by polyIC exclusively in the aged liver. Impaired NR3C1 expression and elevated NF-κB and AP-1 signaling drive a skewing toward Tnf⁺ over Saa1⁺ neutrophils in the aged liver. TNF neutralization rescued polyIC-induced mortality, while also enhancing its antitumor effect in aged mice. Bioinformatic analysis revealed significant association of a Tnf⁺Saa1⁻ neutrophil gene signature with reduced survival in liver cancer patients over 60. This study uncovers a previously unknown detrimental mechanism in the aged liver, which is undetectable under basal conditions. We provide a new strategy to improve therapeutic outcomes in elderly patients by mitigating treatment-associated toxicity.