Li Zhi-Yuan, Ling Yu-Yi, Hao Liang, Shen Qing-Hua, Yu Long-Bo, Wang Peng, Chen Xiao-Xiao, Tan Cai-Ping
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China.
Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, Guangzhou 510006, China.
Anal Chem. 2025 Jul 15;97(27):14741-14749. doi: 10.1021/acs.analchem.5c02337. Epub 2025 Jun 29.
Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are closely linked to immunogenic cell death (ICD), a process critical for eliciting antitumor immune responses. As one of the essential biological elements, zinc plays a pivotal role in regulating cellular immune responses. Herein, we construct a theranostic Ir(III) complex (), which exhibits Zn-responsive phosphorescent properties and specifically localizes to ER. By inducing ER stress through a UPR pathway, further activates ICD, making it an ideal probe to dynamically monitor chelatable Zn during ICD by two-photon phosphorescence lifetime imaging. Moreover, enacts synergistic effects with the programmed death-ligand 1 inhibitor BMS-1 to inhibit cancer growth and improves tumor microenvironment . In conclusion, we report a theranostic Ir(III) complex capable of activating the ER stress and ICD through perturbation of zinc homeostasis and monitoring fluctuations of chelatable Zn in the ER during ICD by two-photon phosphorescence lifetime microscopy, which provides a promising anticancer immunotherapeutic strategy through zinc homeostasis regulation.
内质网（ER）应激和未折叠蛋白反应（UPR）与免疫原性细胞死亡（ICD）密切相关，ICD是引发抗肿瘤免疫反应的关键过程。作为重要的生物元素之一，锌在调节细胞免疫反应中起关键作用。在此，我们构建了一种诊疗一体化的铱（III）配合物（），其具有锌响应磷光特性并特异性定位于内质网。通过UPR途径诱导内质网应激，进一步激活ICD，使其成为通过双光子磷光寿命成像动态监测ICD过程中可螯合锌的理想探针。此外，与程序性死亡配体1抑制剂BMS-1发挥协同作用以抑制癌症生长并改善肿瘤微环境。总之，我们报道了一种诊疗一体化的铱（III）配合物，其能够通过扰乱锌稳态激活内质网应激和ICD，并通过双光子磷光寿命显微镜监测ICD过程中内质网中可螯合锌的波动，这通过锌稳态调节提供了一种有前景的抗癌免疫治疗策略。
