Jing Yang, Ya‐Qian Shi, Song He, Meng-Fan Zhu, Tianxia Wu, Liang-Mei Yang, Wei Zhang, Feng-Yang Wang, Lu Yuan, Liang Hong, Ke-Bin Huang
Abstract Metal-based chemoimmunotherapy has recently attracted considerable interest for its ability to stimulate tumor-specific immunity beyond direct cytotoxic effects. These immunostimulatory outcomes are commonly mediated through immunogenic cell death (ICD). However, metal complex scaffolds capable of eliciting antitumor immune responses through mechanisms other than ICD remain relatively unexplored. In this study, we designed and synthesized six novel half-sandwich Ru(II) complexes featuring an isoquinoline alkaloid-derived C^N ligand, p-cymene, and various 4-pyridyl ancillary ligands. Among these, Ru-4 demonstrated superior cytotoxicity. Mechanistic studies indicated that Ru-4-induced ROS accumulation plays a key role in reducing β-catenin levels, upregulating MHC-I expression, and promoting CCL4 secretion, critical factors for T-cell infiltration and activation. Moreover, its combination with anti-PD1 therapy resulted in synergistic antitumor efficacy. This work represents the first report of a half-sandwich metal-based complex that targets the Wnt/β-catenin pathway to sensitize tumors to immune checkpoint blockade (ICB), offering a novel approach for designing metal-based chemoimmunotherapeutic agents.