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辐射耐药性，增加复发和转移的风险，同时为再次照射提供障碍。使用来自患者和实验小鼠的样本，我们发现 FDX1 和 LIAS 是 cuproptosis 的关键调节因子，在放疗后的残留肿瘤中上调，从而增加了对 cuproptosis 的敏感性。因此，我们提出了一种专注于铜质沉积的新型放射增敏策略，使用含铜纳米胶囊样多金属氧酸盐作为范例。在初步演示中，我们表明纳米胶囊在暴露于电离辐射时以受控方式释放铜离子。此外，即使在临床相关的辐射剂量下，辐射触发的 cuproptosis 也克服了获得性辐射耐药性，并激活了强大的远隔效应，在放射抗性和再照射肿瘤模型中的治愈率均为 40%。总的来说，靶向 cupropsis 是解决获得性辐射耐药性的令人信服的策略，优化放疗的局部抗肿瘤效果，同时激活全身抗肿瘤免疫。