Targeting polyamine metabolism induces oxidative/carbonyl stress to reinvigorate antitumor immunity in prostate cancer

作者：Aijing Zhang, Jianguo Zheng, Yingying Xu, Shuai Fu, Qinglong Du, Chunjian Zhao, Yuxiang Meng, Mengqi Li, Lin Wang, Shuliang Wang, Tongrui Shi, Chen Yang, Peihong Jiang, Yi‐Ping Wang, Zhongwei Zhao, Zhao Zhang, Shuo Zhao, Xin Qin, Huimin Geng, Nengwang Yu · 发表于：Journal of Controlled Release · 年份：2025 · DOI：10.1016/j.jconrel.2025.114283 · 被引用次数：5 · 研究领域：Polyamine Metabolism and Applications、Amino Acid Enzymes and Metabolism、Pancreatic function and diabetes

Immunotherapy of prostate cancer (PCa) remains challenging due to the immunosuppressive nature of the tumor microenvironment (TME). Oxidative damage enhances immunogenic cell death (ICD) to counteract immunotherapy resistance in PCa, but is limited by tumor antioxidant defenses and single-modality reactive oxygen species (ROS) generation in the TME. Herein, we report an innovative polyamine-based strategy that overproduces hydrogen peroxide and acrolein to simultaneously induce oxidative/carbonyl stress while suppressing endogenous antioxidant systems, thereby synergistically amplifying oxidative/carbonyl damage, which triggers robust ICD and achieves potent antitumor efficacy. Both in vitro and in vivo assays demonstrated that the nanoparticles, modified with a PCa-targeting peptide, could generate acrolein to induce mitochondrial destruction, DNA damage, and accumulate lipid peroxidation. In addition, they enhanced the recruitment of mature dendritic cells and T cells within the TME, thus inhibiting lung metastasis and tumor rechallenge. This work proposes an immunotherapy strategy using polyamine metabolism to induce combined carbonyl and oxidative stress, providing a novel approach for overcoming cold TME resistance in advanced PCa.