Sun Xianbin, Wang Xinyi, Li Xudong, Wang Ya, Xu Ruofei, Shen Xinyi, Tan Ding, Liao Jingjing, Chen Haijun, Gao Yu, Zheng Jianping
Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, China.
J Nanobiotechnology. 2025 Jun 5;23(1):419. doi: 10.1186/s12951-025-03486-9.
Reactive oxygen species (ROS)-based nanodynamic therapy is emerging as a promising approach for tumor treatment, particularly in eliciting immune responses for tumor immunotherapy. Nevertheless, the complex tumor microenvironment (TME) and the constraints of current sensitizers substantially compromise therapeutic efficacy. To address these challenges, we developed a rationally designed nanoplatform (LP/CuTT) through lipoic acid-modified orchestrated Cu²⁺-coordinated tetracycline-porphyrin self-assembly, to precisely remodel the immunosuppressive TME while potentiating antitumor immunotherapy via a novel photo-enhanced chemodynamic therapy (CDT) strategy. In vitro studies demonstrated that LP/CuTT-mediated photo-enhanced CDT effectively promoted concurrent apoptosis and cuproptosis in B16-F10 melanoma cells, coupled with robust induction of immunogenic cell death (ICD). Mechanistic investigations revealed that LP/CuTT drives macrophage polarization from tumor-promoting M2 to antitumor M1 phenotypes while promoting dendritic cell (DC) maturation, thereby orchestrating potent antitumor immune responses. In vivo evaluations showed preferential tumor accumulation of LP/CuTT, correlating with substantial ROS generation at tumor sites and remarkable therapeutic outcomes. Quantitative assessments further demonstrated elevated M1 macrophage infiltration in both tumor and splenic tissues, accompanied by enhanced CD8 and CD4 T cell recruitment. These findings provide key insights into developing orchestrated metal-coordinated nanotherapeutics by repurposing existing therapeutic agents, enabling the design of multifunctional systems that integrate efficient chemodynamic activity, TME remodeling, and immune activation for effective nanodynamic therapy.
The online version contains supplementary material available at 10.1186/s12951-025-03486-9.
基于活性氧（ROS）的纳米动力学疗法正在成为一种有前景的肿瘤治疗方法，特别是在引发肿瘤免疫治疗的免疫反应方面。然而，复杂的肿瘤微环境（TME）和当前敏化剂的局限性严重影响了治疗效果。为了应对这些挑战，我们通过硫辛酸修饰的精心设计的Cu²⁺配位四环素-卟啉自组装开发了一种合理设计的纳米平台（LP/CuTT），以精确重塑免疫抑制性TME，同时通过一种新型的光增强化学动力学疗法（CDT）策略增强抗肿瘤免疫治疗。体外研究表明，LP/CuTT介导的光增强CDT有效地促进了B16-F10黑色素瘤细胞中同时发生的凋亡和铜死亡，同时强烈诱导免疫原性细胞死亡（ICD）。机制研究表明，LP/CuTT驱动巨噬细胞从促肿瘤的M2表型向抗肿瘤的M1表型极化，同时促进树突状细胞（DC）成熟，从而协调强大的抗肿瘤免疫反应。体内评估显示LP/CuTT在肿瘤中优先积累，与肿瘤部位大量ROS生成和显著的治疗效果相关。定量评估进一步表明，肿瘤和脾脏组织中M1巨噬细胞浸润增加，同时CD8和CD4 T细胞募集增强。这些发现为通过重新利用现有治疗剂开发精心设计的金属配位纳米治疗剂提供了关键见解，从而能够设计出整合高效化学动力学活性、TME重塑和免疫激活的多功能系统，以实现有效的纳米动力学治疗。
在线版本包含可在10.1186/s12951-025-03486-9获取的补充材料。
