Liu, YanbiaoPark, SeohyunLi, Yan2025-06-302025-06-302025-06-11Cancers (Basel), ISSN: 2072-6694 (Print); 2072-6694 (Online), MDPI AG, 17(12), 1941-1941. doi: 10.3390/cancers171219412072-66942072-6694http://hdl.handle.net/10292/19424CDK4/6 inhibition represents a new generation of cancer therapies, targeting CDK4/6 complexes to induce cell cycle arrest in the G1 phase. These inhibitors have been widely used in combination with hormone receptor antagonists for treating ER+/HER2- breast cancer, achieving significant clinical success. Building on this progress, ongoing research explores novel combination therapies and expands the application of CDK4/6 inhibitors to other diseases. However, challenges remain, including variable cellular responses and the rapid development of drug resistance. Recent studies have uncovered new resistance mechanisms and their unexpected effects on cell metabolism, autophagy, and the tumor microenvironment beyond cell cycle arrest. This review provides a comprehensive overview of the mechanisms by which CDK4/6 inhibitors combat cancer and explores their potential for more effective and personalized treatment strategies.© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).https://creativecommons.org/licenses/by/4.0/CDK 4/6 inhibitorcancer treatmentcombination therapy32 Biomedical and Clinical Sciences3211 Oncology and CarcinogenesisCancerWomen's HealthBreast Cancer5.1 Pharmaceuticals6.1 Pharmaceuticals2.1 Biological and endogenous factorsCancer3 Good Health and Well Being1112 Oncology and Carcinogenesis3211 Oncology and carcinogenesisJournal ArticleOpenAccess10.3390/cancers17121941