Targeting the cell-cycle machinery for cancer therapy.

The cell cycle is governed by tightly regulated checkpoints and proteogenomic oscillations that ensure genomic fidelity during cell proliferation. Dysregulation of the cell cycle can drive oncogenic transformation, and this positions it as a pivotal target in precision oncology. Recent advances reveal how proteomic and post-translational dynamics orchestrate cell-cycle phase transitions that are aberrantly disrupted in cancers. Therapeutic targeting of the CDK4/6 represents a cornerstone of cancer therapy, but resistance mechanisms limit its clinical efficacy. Emerging strategies such as targeted protein degradation, synthetic lethality, and combination immunotherapies further expand the therapeutic window. These innovations, coupled with biomarker-driven precision medicine, exploit cell-cycle vulnerabilities and transform them into an active tool to combat human cancers more effectively. This review highlights emerging mechanistic insights underlying tumorigenesis driven by an aberrant cell cycle and proposes potential therapeutics aimed at cell-cycle machinery-relevant targets.