Liao You, Wang Dongmei, Gu Chenglu, Wang Xue, Zhu Shuang, Zheng Ziye, Zhang Fuquan, Yan Junfang, Gu Zhanjun
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China.
College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, China.
Nat Nanotechnol. 2024 Dec;19(12):1892-1902. doi: 10.1038/s41565-024-01784-1. Epub 2024 Sep 19.
Residual tumours that persist after radiotherapy often develop acquired radiation resistance, increasing the risk of recurrence and metastasis while providing obstacles to re-irradiation. Using samples from patients and experimental mice, we discovered that FDX1 and LIAS, key regulators of cuproptosis, were up-regulated in residual tumours following radiotherapy, conferring the increased sensitivity to cuproptosis. Therefore, we proposed a novel radiosensitization strategy focused on cuproptosis, using a copper-containing nanocapsule-like polyoxometalate as a paradigm. In an initial demonstration, we showed that the nanocapsule released copper ions in a controlled manner upon exposure to ionizing radiation. Furthermore, radiation-triggered cuproptosis overcame acquired radiation resistance even at clinically relevant radiation doses and activated a robust abscopal effect, with a 40% cure rate in both radioresistant and re-irradiation tumour models. Collectively, targeting cuproptosis is a compelling strategy for addressing acquired radiation resistance, optimizing the local antitumour effects of radiotherapy while simultaneously activating systemic antitumour immunity.
放疗后持续存在的残留肿瘤通常会产生获得性放射抗性，增加复发和转移风险，同时给再次放疗带来障碍。利用患者样本和实验小鼠，我们发现铜死亡的关键调节因子FDX1和LIAS在放疗后的残留肿瘤中上调，使肿瘤对铜死亡的敏感性增加。因此，我们提出了一种以铜死亡为重点的新型放射增敏策略，以含铜纳米胶囊状多金属氧酸盐为范例。在初步验证中，我们表明该纳米胶囊在暴露于电离辐射时以可控方式释放铜离子。此外，辐射触发的铜死亡即使在临床相关辐射剂量下也能克服获得性放射抗性，并激活强大的远隔效应，在放射抗性和再次放疗肿瘤模型中的治愈率均为40%。总的来说，靶向铜死亡是解决获得性放射抗性、优化放疗局部抗肿瘤效果同时激活全身抗肿瘤免疫的一种有吸引力的策略。
