Triple-Synergistic Therapy with Cobalt-Pheophytin Coordination Micelles for Overcoming Drug Resistance in Pancreatic Cancers.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies as KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations continuously activate multiple downstream signaling pathways, leading to drug resistance. To overcome this issue, herein, we developed a cobalt-pheophytin (CoPheo) coordination micelle chelating two chemotherapeutic agents including ONC201 and Palbociclib (Pal), yielding CoPheo-ONC201-Pal-F127. Compared with other metals, cobalt exhibits stronger coordination ability and higher drug-loading efficiency. The resulting ligand bonds are both acid- and GSH-responsive so that the cargos could be responsively released in the tumor microenvironment. To overcome drug resistance in KRAS-mutant cancers, CoPheo-ONC201-Pal-F127 is able to regulate three independent cell death pathways including ferroptosis, disulfidptosis, and cellular senescence. In particular, the cobalt-mediated Fenton-like effect synergistically enhances ONC201-induced serine-threonine protein kinase AKT (AKT) inhibition to amplify ferroptosis. Also, cobalt-mediated NADPH oxidation disrupts redox homeostasis in synergy with Pal-induced NADPH depletion, triggering disulfidptosis. In addition, ONC201-mediated mitogen-activated protein kinase kinase (MEK) inhibition, combined with Pal-induced CDK4/6 blockade, promotes cellular senescence and remodels the tumor microenvironment. These three independent mechanisms collectively establish a mutually enhanced therapeutic strategy capable of overcoming the complex drug resistance driven by multiple downstream signaling pathways in KRAS-mutant pancreatic cancer.