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-p-cym)(BTBpy)Cl] (RuBTB) is developed for ferroptosis-enhanced antitumor immunity and drug
resistance reversal via glutathione (GSH) metabolism imbalance. RuBTB 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 RuBTB-treated cells. Mechanism studies indicate that RuBTB 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.