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

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