Isoquinoline-Derived Half-Sandwich Ru(II) Arene Complex Potentiates Antitumor Chemoimmunotherapeutic Response

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.