Intermetallics triggering pyroptosis and disulfidptosis in cancer cells promote anti-tumor immunity

Yanlin Zhu, Xinxin Wang, Lili Feng (), Ruoxi Zhao, Can Yu, Yuanli Liu, Ying Xie, Bin Liu, Yang Zhou () and Piaoping Yang ()
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Yanlin Zhu: Harbin Engineering University
Xinxin Wang: Harbin Medical University Cancer Hospital
Lili Feng: Harbin Engineering University
Ruoxi Zhao: Harbin Engineering University
Can Yu: Harbin Medical University Cancer Hospital
Yuanli Liu: Harbin Medical University
Ying Xie: Heilongjiang University
Bin Liu: Harbin Engineering University
Yang Zhou: Harbin Medical University Cancer Hospital
Piaoping Yang: Harbin Engineering University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Pyroptosis, an immunogenic programmed cell death, could efficiently activate tumor immunogenicity and reprogram immunosuppressive microenvironment for boosting cancer immunotherapy. However, the overexpression of SLC7A11 promotes glutathione biosynthesis for maintaining redox balance and countering pyroptosis. Herein, we develop intermetallics modified with glucose oxidase (GOx) and soybean phospholipid (SP) as pyroptosis promoters (Pd2Sn@GOx-SP), that not only induce pyroptosis by cascade biocatalysis for remodeling tumor microenvironment and facilitating tumor cell immunogenicity, but also trigger disulfidptosis mediated by cystine accumulation to further promote tumor pyroptosis in female mice. Experiments and density functional theory calculations show that Pd2Sn nanorods with an intermediate size exhibit stronger photothermal and enzyme catalytic activity compared with the other three morphologies investigated. The peroxidase-mimic and oxidase-mimic activities of Pd2Sn cause potent reactive oxygen species (ROS) storms for triggering pyroptosis, which could be self-reinforced by photothermal effect, hydrogen peroxide supply accompanied by glycometabolism, and oxygen production from catalase-mimic activity of Pd2Sn. Moreover, the increase of NADP+/NADPH ratio induced by glucose starvation could pose excessive cystine accumulation and inhibit glutathione synthesis, which could cause disulfidptosis and further augment ROS-mediated pyroptosis, respectively. This two-pronged treatment strategy could represent an alternative therapeutic approach to expand anti-tumor immunotherapy.

Date: 2024
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DOI: 10.1038/s41467-024-53135-2

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