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

Chemoresistance remains an arduous challenge in oncology, but ferroptosis shows potential for overcoming it by stimulating the immune system. Herein, a novel high-performance ruthenium(II)-based arene complex [Ru(η⁶-<i>p</i>-cym)(BTBpy)Cl] (<b>RuBTB</b>) is developed for ferroptosis-enhanced antitumor immunity and drug resistance reversal via glutathione (GSH) metabolism imbalance. <b>RuBTB</b> shows significantly enhanced antiproliferation activity against cisplatin (CDDP)-resistant lung cancer cells (A549R), with 26.35-fold better anticancer effects than CDDP. Immunogenic ferroptosis is induced by GSH depletion/glutathione peroxidase 4 (GPX4) inactivation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in <b>RuBTB</b>-treated cells. Mechanism studies indicate that <b>RuBTB</b> regulates ferroptosis and immune-related pathways, coordinating with GSH metabolism-mediated glutathione S-transferase (GST) inhibition to reverse drug resistance in platinum-combined therapy. Tumor vaccination experiments demonstrate the intensified antitumor effects endowed by highly immunogenic ferroptosis in vivo. This study provides the first example of a metal-arene complex for achieving satisfactory ferroptosis therapeutic effects with efficient immunogenicity to overcome drug resistance in metal-based immunochemotherapy.