Cheng Haipeng, Zhao Lin, Cai Jing
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China.
Mater Today Bio. 2025 May 21;32:101894. doi: 10.1016/j.mtbio.2025.101894. eCollection 2025 Jun.
Cuproptosis, a novel copper-dependent regulated cell death mechanism, represents a paradigm shift in oncology by exploiting unique copper dyshomeostasis mechanisms to combat intractable malignancies. While cuproptosis-based therapies hold transformative potential for diverse cancers, their clinical translation is hindered by inherent limitations, including suboptimal immunostimulatory efficacy, insufficient tumor specificity, and immunosuppressive crosstalk within the tumor microenvironment. Recent breakthroughs in nanotechnology have unlocked revolutionary strategies to address these challenges, with copper-based nanotherapeutic systems emerging as precision tools to amplify cuproptosis efficacy. Engineered nanosystems circumvent critical barriers of conventional small-molecule drugs, such as off-target toxicity and pharmacokinetic instability, by enabling spatiotemporal control of copper delivery, microenvironment remodeling, and synergistic activation of cell death cascades. This review systematically examines cutting-edge advances in nanomaterial design for potentiating cuproptosis, emphasizing three transformative frontiers: (1) combinatorial cell death modalities integrating cuproptosis with apoptosis, ferroptosis, or pyroptosis for amplified therapeutic cascades; (2) multimodal nanoplatforms coupling cuproptosis inducers with various treatment modalities to overcome resistance; and (3) precision-targeted delivery systems utilizing ligand/receptor engineering and stimuli-responsive materials for tumor-selective copper overload. Finally, further mechanistic insights into nanomaterial-triggered cuproptosis and its immunomodulatory consequences within tumor niches are critically evaluated.
铜死亡是一种新型的铜依赖性调控细胞死亡机制，通过利用独特的铜稳态失衡机制来对抗难治性恶性肿瘤，代表了肿瘤学领域的范式转变。虽然基于铜死亡的疗法对多种癌症具有变革潜力，但其临床转化受到固有局限性的阻碍，包括免疫刺激效果欠佳、肿瘤特异性不足以及肿瘤微环境内的免疫抑制相互作用。纳米技术的最新突破开启了应对这些挑战的革命性策略，基于铜的纳米治疗系统作为增强铜死亡疗效的精准工具应运而生。工程化纳米系统通过实现铜递送的时空控制、微环境重塑以及细胞死亡级联反应的协同激活，规避了传统小分子药物的关键障碍，如脱靶毒性和药代动力学不稳定性。本综述系统地研究了用于增强铜死亡的纳米材料设计的前沿进展，重点强调了三个变革性前沿领域：（1）将铜死亡与凋亡、铁死亡或焦亡整合的组合性细胞死亡模式，以放大治疗级联反应；（2）将铜死亡诱导剂与各种治疗模式相结合的多模态纳米平台，以克服耐药性；（3）利用配体/受体工程和刺激响应材料实现肿瘤选择性铜过载的精准靶向递送系统。最后，对纳米材料引发的铜死亡及其在肿瘤微环境中的免疫调节后果的进一步机制见解进行了批判性评估。
