Ruthenium(ii)–Arene\nComplex Triggers Immunogenic\nFerroptosis for Reversing Drug Resistance

Chemoresistance remains an arduous challenge in oncology,\nbut ferroptosis\nshows potential for overcoming it by stimulating the immune system.\nHerein, a novel high-performance ruthenium(II)-based arene complex\n[Ru(η<sup>6</sup>-<i>p</i>-cym)(BTBpy)Cl] (<b>RuBTB</b>) is developed for ferroptosis-enhanced antitumor immunity and drug\nresistance reversal via glutathione (GSH) metabolism imbalance. <b>RuBTB</b> shows significantly enhanced antiproliferation activity\nagainst cisplatin (CDDP)-resistant lung cancer cells (A549R), with\n26.35-fold better anticancer effects than CDDP. Immunogenic ferroptosis\nis induced by GSH depletion/glutathione peroxidase 4 (GPX4) inactivation,\nmitochondrial 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\nwith GSH metabolism-mediated glutathione S-transferase (GST) inhibition\nto reverse drug resistance in platinum-combined therapy. Tumor vaccination\nexperiments demonstrate the intensified antitumor effects endowed\nby highly immunogenic ferroptosis in vivo. This study provides the\nfirst example of a metal–arene complex for achieving satisfactory\nferroptosis therapeutic effects with efficient immunogenicity to overcome\ndrug resistance in metal-based immunochemotherapy.