Dynamic Monitoring of Chelatable Zinc on Endoplasmic Reticulum During Immunogenic Cell Death by TPPLIM Using a Theranostic Ir(III) Complex

Zhi-Yuan Li; Yu-Yi Ling; Liang Hao; Qing-Hua Shen; Long-Bo Yu; Peng Wang; Xiao-Xiao Chen; Cai-Ping Tan

doi:10.1021/acs.analchem.5c02337

Dynamic Monitoring of Chelatable Zinc on Endoplasmic Reticulum During Immunogenic Cell Death by TPPLIM Using a Theranostic Ir(III) Complex

Anal Chem. 2025 Jun 29. doi: 10.1021/acs.analchem.5c02337. Online ahead of print.

Authors

Zhi-Yuan Li^{1

2}, Yu-Yi Ling^{1

3

2}, Liang Hao^{1

2}, Qing-Hua Shen^{1

2}, Long-Bo Yu^{1

2}, Peng Wang^{1

2}, Xiao-Xiao Chen^{1

2}, Cai-Ping Tan^{1

2

4}

Affiliations

¹ MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China.
² Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, Guangzhou 510006, China.
³ The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical-Medicine, Guangdong Medical University, Zhanjiang, Guangdong 524023, China.
⁴ State Key Laboratory of Anti-Infective Drug Discovery and Development; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

PMID: 40583441
DOI: 10.1021/acs.analchem.5c02337

Abstract

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 (Ir-ER-Zn), which exhibits Zn²⁺-responsive phosphorescent properties and specifically localizes to ER. By inducing ER stress through a UPR pathway, Ir-ER-Zn further activates ICD, making it an ideal probe to dynamically monitor chelatable Zn²⁺ during ICD by two-photon phosphorescence lifetime imaging. Moreover, Ir-ER-Zn enacts synergistic effects with the programmed death-ligand 1 inhibitor BMS-1 to inhibit cancer growth and improves tumor microenvironment in vivo. 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 Zn²⁺ in the ER during ICD by two-photon phosphorescence lifetime microscopy, which provides a promising anticancer immunotherapeutic strategy through zinc homeostasis regulation.