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Multipronged Protein Engagement by a Ruthenium(II) Sunitinib Hydrazide Complex Elicits ROS-Independent Immunogenic
Shilpendu Ghosh1, Soumee SenGupta2, Ratan Halder3
1Department of Chemical Sciences and Centre for Advanced Functional Materials (CAFM), Indian Institute of Science Education and Research Kolkata, Mohanpur, India.
Angewandte Chemie (International Ed. in English)
|July 25, 2026
Summary
This study introduces a novel metal complex that triggers cancer cell death without increasing reactive oxygen species (ROS). This new approach targets NF-κB, VEGFR2, and telomerase, enhancing anti-tumor immunity.
Area of Science:
- Metal-based cancer therapy
- Immunogenic cell death (ICD) induction
- Reactive oxygen species (ROS) independent pathways
Background:
- Current metal-based immunogenic cell death (ICD) inducers often rely on elevated reactive oxygen species (ROS) to induce endoplasmic reticulum (ER) stress.
- NF-κB signaling amplifies oxidative stress and promotes pro-tumorigenic signaling, posing a challenge for ROS-driven ICD strategies.
Purpose of the Study:
- To develop a novel strategy for inducing ICD independently of ROS.
- To investigate a Ru(II)-sunitinib hydrazide complex (5) for its ability to inhibit NF-κB signaling, VEGFR2 phosphorylation, and telomerase activity.
- To evaluate the efficacy of targeted delivery of the complex (5@PFC) in a tumor model.
Main Methods:
- Synthesis of a Ru(II)-sunitinib hydrazide complex (5) from a sunitinib derivative.
- Assessment of NF-κB signaling inhibition (p65 phosphorylation, nuclear translocation).
- Measurement of VEGFR2 phosphorylation and telomerase activity (TRAP assay).
- Evaluation of intracellular ROS levels and ER-mitochondrial stress.
- In vivo studies using folate-targeted micellar delivery (5@PFC) in 4T1 tumor-bearing mice.
Main Results:
- Complex 5 inhibited NF-κB signaling, VEGFR2 phosphorylation, and telomerase activity without increasing intracellular ROS.
- Simultaneous inhibition of VEGFR2, NF-κB, and telomerase induced non-oxidative ER-mitochondrial stress, leading to DAMP release and apoptotic ICD.
- Folate-targeted delivery (5@PFC) enhanced tumor selectivity and suppressed tumor growth in mice.
- 5@PFC treatment increased the intratumoral CD4:CD8 ratio, indicating enhanced immune activation.
Conclusions:
- The Ru(II)-sunitinib hydrazide complex represents a novel ROS-independent ICD inducer.
- Targeted delivery of the complex enhances anti-tumor efficacy and promotes immune activation.
- This strategy offers a promising alternative to conventional ROS-driven cancer therapies.
