Ruthenium(ii)-Arene Complex Triggers Immunogenic Ferroptosis for Reversing Drug Resistance

Area of Science:

• Metal-based chemotherapy
• Immunogenic cell death
• Cancer drug resistance

Background:

• Chemoresistance is a major obstacle in cancer treatment.
• Ferroptosis, a form of regulated cell death, presents a promising avenue for overcoming chemoresistance by engaging the immune system.
• Metal-arene complexes offer unique therapeutic potential in oncology.

Purpose of the Study:

• To develop a novel ruthenium(II)-based arene complex, RuBTB, for ferroptosis-enhanced antitumor immunity and drug resistance reversal.
• To investigate the mechanisms by which RuBTB induces ferroptosis and modulates glutathione metabolism.
• To evaluate the in vivo efficacy of RuBTB in combination with platinum-based therapy.

Main Methods:

• Synthesis and characterization of the ruthenium(II)-based arene complex [Ru(η⁶-p-cym)(BTBpy)Cl] (RuBTB).
• In vitro antiproliferation assays using cisplatin-resistant lung cancer cells (A549R).
• Mechanistic studies involving glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and glutathione S-transferase (GST) inhibition.
• In vivo tumor vaccination experiments to assess antitumor effects.

Main Results:

• RuBTB demonstrated significantly enhanced antiproliferation activity against cisplatin-resistant lung cancer cells (26.35-fold greater than CDDP).
• RuBTB induced immunogenic ferroptosis via GSH depletion/GPX4 inactivation, mitochondrial dysfunction, and ER stress.
• RuBTB reversed platinum drug resistance by inhibiting GST, thereby modulating GSH metabolism and enhancing immune responses.
• In vivo tumor vaccination confirmed intensified antitumor effects due to RuBTB-induced immunogenic ferroptosis.

Conclusions:

• The developed RuBTB complex is a high-performance agent for ferroptosis-enhanced antitumor immunity and drug resistance reversal.
• RuBTB effectively targets glutathione metabolism to overcome chemoresistance in platinum-combined therapy.
• This study presents the first metal-arene complex capable of inducing potent ferroptosis with significant immunogenicity to combat drug resistance in metal-based immunochemotherapy.