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

ABSTRACT 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.