{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:22:17Z","timestamp":1783527737712,"version":"3.55.0"},"reference-count":142,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pharmacological cyclin-dependent kinase 4 and 6 (CDK4\/6) inhibitors have reshaped the treatment landscape of HR-positive, HER2-negative (HR+\/HER2\u2212) 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.<\/jats:p>","DOI":"10.3390\/cancers18142192","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:40:09Z","timestamp":1783525209000},"page":"2192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDK4\/6 Inhibitor-Induced Senescence in Cancer: Mechanisms and Therapeutic Implications"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2675-7400","authenticated-orcid":false,"given":"Simin Elif","family":"T\u00fcrker","sequence":"first","affiliation":[{"name":"European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG), 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-4813","authenticated-orcid":false,"given":"Marco","family":"Demaria","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG), 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-6714","authenticated-orcid":false,"given":"Boshi","family":"Wang","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG), 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1038\/s41417-024-00747-x","article-title":"Recent progress of CDK4\/6 inhibitors\u2019 current practice in breast cancer","volume":"31","author":"Wang","year":"2024","journal-title":"Cancer Gene Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s11912-019-0769-3","article-title":"CDK 4\/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions","volume":"21","author":"Spring","year":"2019","journal-title":"Curr. 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