Abstract 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 TNFα 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. Citation Format: Jin Lee, Yiming Gao, Yufei Zhang, Aaron Havas, Peter Adams, Gerald S. Shadel, Susan M. Kaech, Gen-Sheng Feng. A TNF-producing neutrophil subset drives age-dependent hepatotoxicity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 169.
Lee et al. (Fri,) studied this question.