CDK4/6 Inhibitor-Induced Senescence in Cancer: Mechanisms and Therapeutic Implications.

Pharmacological cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have reshaped the treatment landscape of HR-positive, HER2-negative (HR+/HER2-) breast cancer and are increasingly being explored across diverse malignancies. By preventing retinoblastoma (RB) phosphorylation and enforcing G1-S cell cycle arrest, these agents achieve durable tumour control with a more favourable toxicity profile than conventional chemotherapy. Beyond their canonical cytostatic effects, prolonged CDK4/6 inhibitor treatments induce cellular senescence, a stable, proliferative arrest accompanied by profound transcriptional, epigenetic, and secretory changes. This review summarises current knowledge on CDK4/6 inhibitor-induced senescence in both cancer and normal cells as a central biological mechanism that links tumour suppression and microenvironmental remodelling. Importantly, this process is highly context-dependent, differing between tumour and non-malignant cells, with a distinct senescence-associated secretory phenotype (SASP) that shapes immune responses and tissue homeostasis. We also discuss how CDK4/6 inhibitor-induced senescence influences the tumour microenvironment by modulating immune surveillance, stromal interactions, and cancer cell plasticity. Finally, we examine emerging resistance mechanisms and rational combination strategies for CDK4/6 inhibitors, including targeting compensatory signalling pathways, immune checkpoint blockades, and senescence-directed sequential therapies. Collectively, CDK4/6 inhibitor-induced senescence represents both a challenge and a therapeutic opportunity, underscoring the need to integrate cell cycle control with the modulation of cellular states.