Cyclin-dependent kinases as therapeutic targets in cancer: Recent advances, challenges, and opportunities.

Dysregulated cell cycle progression drives uncontrolled proliferation and is a fundamental hallmark of cancer, making cyclin-dependent kinases (CDKs), which largely govern cell-cycle progression and cell division, attractive therapeutic targets. Currently, CDK inhibitors (CDKIs), particularly agents targeting CDK4/6, have shown clinical activity in HR+/HER2-metastatic breast cancer. Recent structural elucidation of the CDK2 catalytic domain and its allosteric sites has enabled the development of several selective CDK2 inhibitors, many of which have exhibited encouraging antitumor activity. Moreover, emerging evidence further indicates that dual inhibition of CDK4/6 and CDK2 can synergistically overcome resistance to CDK4/6 blockade. Notably, recent studies have revealed that CDKIs can induce cellular senescence and enhance the efficacy of cancer immunotherapy. In this review, we outline the CDK family and their key functions in cell cycle control, summarize recent clinical advances in CDKI-based therapies, with emphasis on CDK4/6 and CDK2 inhibition, and discuss opportunities to integrate CDK-targeted therapy with immunotherapy and other therapeutic strategies.