Deng Wen, Zhong Zichen, Shang Haojie, Tong Yonghua, Huang Qiu, He Yu, Wu Jian, Ba Xiaozhuo, Chen Zhiqiang, Chen Yuan, Tang Kun
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Nanobiotechnology. 2025 Jul 28;23(1):544. doi: 10.1186/s12951-025-03616-3.
Immunotherapy is a highly promising cancer treatment method. However, it is limited by low immunogenicity and an immunosuppressive microenvironment, which could be relieved by immunogenic cell death (ICD). Currently, effective ICD is primarily achieved through apoptosis induction, but tumor cells' resistance to apoptosis limits its antitumor efficacy. Therefore, developing new cell death modalities with high immunogenicity for cancer immunotherapy is of great significance. Cuproptosis, a newly discovered form of programmed cell death, can effectively circumvent tumor cells' resistance to apoptosis. Various Cu ionophores have been studied as anticancer drugs to promote cuproptosis, but the lack of tumor specificity remains one of the major challenges in this field. In contrast, nanoparticles tend to preferentially accumulate in tumor tissues due to the enhanced permeability and retention (EPR) effect, and they can be surface-modified to achieve active tumor targeting capabilities. Recently, many unique physicochemical properties of nanoparticles have been designed as nano-inducers of cuproptosis, successfully enhancing immunotherapy. Based on this, this review detailedly summarized various strategies and applications of nanoparticles-induced cuproptosis in tumor cells. The role of Cu metabolism and homeostasis in tumorigenesis and development, the molecular mechanisms of cuproptosis and different cuproptosis inducers with promising application prospects, as well as the interaction between cuproptosis and immunotherapy have also been reviewed. Finally, we presented the limitations and future prospects of cuproptosis nano-inducers, hoping to provide a new strategy to enhance antitumor immunotherapy.
免疫疗法是一种极具前景的癌症治疗方法。然而，它受到低免疫原性和免疫抑制微环境的限制，而免疫原性细胞死亡（ICD）可以缓解这些问题。目前，有效的ICD主要通过诱导凋亡来实现，但肿瘤细胞对凋亡的抗性限制了其抗肿瘤疗效。因此，开发具有高免疫原性的新型细胞死亡方式用于癌症免疫治疗具有重要意义。铜死亡是一种新发现的程序性细胞死亡形式，能够有效规避肿瘤细胞对凋亡的抗性。各种铜离子载体已作为抗癌药物进行研究以促进铜死亡，但缺乏肿瘤特异性仍然是该领域的主要挑战之一。相比之下，由于增强的渗透和滞留（EPR）效应，纳米颗粒倾向于优先在肿瘤组织中积累，并且可以进行表面修饰以实现主动肿瘤靶向能力。最近，许多独特的纳米颗粒物理化学性质已被设计为铜死亡的纳米诱导剂，成功增强了免疫治疗效果。基于此，本综述详细总结了纳米颗粒诱导肿瘤细胞铜死亡的各种策略和应用。还综述了铜代谢和稳态在肿瘤发生发展中的作用、铜死亡的分子机制以及具有广阔应用前景的不同铜死亡诱导剂，以及铜死亡与免疫治疗之间的相互作用。最后，我们阐述了铜死亡纳米诱导剂的局限性和未来前景，希望能为增强抗肿瘤免疫治疗提供一种新策略。
