Senescence-Primed Ferroptosis Enabled by a Metal-Organic Framework Nanoplatform for Enhanced Cancer Therapy.

Abstract

Inhibition of cyclin-dependent kinases (CDKs) offers a promising approach for selective cancer therapy by arresting aberrant cell proliferation and inducing tumor cell senescence. However, the limited efficacy and acquired resistance resulting from primarily cytostatic rather than cytotoxic effects have hindered broader clinical applications. To overcome these limitations, we propose a senescence-primed ferroptosis strategy using a metal-organic framework (MOF)-based nanoplatform (ZPG) that codelivers CDK4/6 inhibitor (palbociclib) and ferroptosis inducer (gallium ions, Ga³⁺) to enhance antitumor efficacy. ZPG exhibited excellent physiological stability, improved cellular uptake, and controlled drug release. In oral squamous cell carcinoma (OSCC) cells with CDK4/6 hyperactivity, palbociclib selectively blocks cell-cycle progression and induces robust senescence, leading to downregulation of antiferroptosis factors (GPX4 and GSH) and upregulation of pro-ferroptosis factors (ACSL4 and Fe²⁺ accumulation). Such redox reprogramming compromises cellular antioxidant defenses and promotes lipid peroxidation, thereby sensitizing senescent cells to ferroptosis. Meanwhile, Ga³⁺ mimics Fe³⁺ in protein binding and disrupts iron metabolism, further amplifying ferroptotic stress and promoting selective ferroptosis in senescent tumor cells. Leveraging ZPG for the codelivery of therapeutic agents, the synergistic mechanism resulted in markedly enhanced antitumor efficacy both <i>in vitro</i> and <i>in vivo</i>, with minimal off-target toxicity. Collectively, the ZPG-enabled senescence-primed ferroptosis strategy provides a promising and mechanistically rational approach for improving cancer therapy.