Multipronged Protein Engagement by a Ruthenium(II) Sunitinib Hydrazide Complex Elicits ROS‐Independent Immunogenic Cell Death

Metal-based immunogenic cell death (ICD) inducers commonly rely on elevated reactive oxygen species (ROS) to trigger endoplasmic reticulum (ER) stress. The central regulator of inflammatory signaling, NF-κB, can amplify oxidative stress responses and promote pro-tumorigenic signaling. Thus, strategies that induce ICD independently of ROS may represent a conceptual shift from ROS-driven paradigms. Here we show that using a hydrazide derivative of a clinical angiogenesis inhibitor sunitinib to form a Ru(II)-sunitinib hydrazide complex (5) inhibits NF-κB signaling (reduced p65 phosphorylation and blocked p50-p65 nuclear translocation), suppresses VEGFR2 phosphorylation, and decreases telomerase activity (cell-free TRAP assay), thereby redirecting cellular responses toward apoptotic ICD. The sunitinib hydrazide provides the VEGFR2 and telomerase inhibition properties but it also promotes NF-κB (p50-p65) nuclear translocation and ROS generation. In contrast, the intracellular ROS levels remain largely unchanged with 5 which inhibits the NF-κB pathway. Simultaneous inhibition of VEGFR2, NF-κB, and telomerase enforces sustained non-oxidative ER-mitochondrial stress, triggering DAMP release and apoptotic immunogenic cell death. Folate-targeted PEG-PCL micellar delivery (5@PFC) improves tumor selectivity fourfold and suppresses tumor growth in immunocompetent 4T1 mice, accompanied by an increased intratumoral CD4:CD8 ratio, indicating enhanced immune activation.