Stable Cyclometalated Gold(III) Complex Engaging Isoquinoline Derivative and Disulfur Ligand Elicits Necroptosis-Dependent Immunogenic Cell Death

Cancer chemoimmunotherapy based on metal complexes has attracted wide interest for its ability to eliminate tumor cells while activating antitumor immunity, primarily by inducing immunogenic cell death (ICD). However, clinical translation of ICD inducers remains challenging, underscoring the need for inducers that elicit ICD via alternative cell death mechanisms. Necroptosis represents a potent yet underutilized route to trigger ICD. Herein, we designed a series of stable Au(III) complexes incorporating an isoquinoline-derived cyclometalated C^N ligand and various strong electron-donating S^S or N^N auxiliary ligands. Among them, Au-1 exhibited potent cytotoxicity, inhibited thioredoxin reductase (TrxR), elevated intracellular ROS, and triggered ROS-mediated Necroptosis. This process elicited robust necroptosis-dependent ICD. In vivo, Au-1 significantly suppressed tumor growth, remodeled the tumor immune microenvironment, and synergized effectively with anti-PD-1 therapy. This work presents the first rationally designed cyclometalated Au(III) complex that functions as a necroptosis-dependent ICD inducer, offering a promising strategy for metal-based chemoimmunotherapy.