Leveraging a Multienzymes‐Mimicking Nanozyme to Overcome CDK4/6 Inhibitor Resistance and Achieve Drug Repurposing in Oesophageal Squamous Cell Carcinoma

ABSTRACT Cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitors, approved as checkpoint blockers for breast cancer therapy, have recently been investigated for oesophageal squamous cell carcinoma (OSCC), as it frequently harbors genetic alterations in cell cycle regulators. However, a phase II clinical trial showed no objective responses in OSCC, underscoring the critical challenge of drug resistance. Our findings reveal that the CDK4/6 inhibitors induce pan‐ERBB pathway activation and glutathione peroxidase 4 (GPX4) overexpression, which promote cellular metabolism and reduce sensitivity to apoptosis and ferroptosis. Together with these findings, we developed a CDK4/6 inhibitor‐loaded nano‐palladium supported single‐layer CoAl layered double hydroxide (Pd/s‐CALDH@Palbo) nanozyme. Pd/s‐CALDH@Palbo exhibits multienzymes‐mimicking activity and is capable of generating reactive oxygen species to synergize with CDK4/6 blockade. A series of in vitro and in vivo studies demonstrate that Pd/s‐CALDH@Palbo suppresses pan‐ERBB pathway activation and GPX4 overexpression, reduces cellular metabolism, and triggers apoptosis and ferroptosis, thereby effectively overcoming CDK4/6 inhibitor resistance and demonstrating potent antitumor efficacy in OSCC. Overall, our work presents a nanozyme‐mediated drug repurposing paradigm, with potential applications in precision medicine.