Abstract:The standard first-line treatment for advanced hormone receptor-positive（HR+），human epidermal growth factor receptor 2negative（HER2-）breast cancer is the combination of cyclin-dependent kinase 4/6（CDK4/6）inhibitors and endocrine therapy，whichsignificantly prolongs patients?? progression-free survival. However，clinical resistance to CDK4/6 inhibitors severely impacts patients ??prognosis. The resistance mechanisms of CDK4/6 inhibitors are complex，involving multiple dimensions such as abnormal cell cycleregulation，activation of growth factor receptors and signaling pathways，abnormal immune regulation，and autophagy activation.Current strategies to address resistance include diverse approaches：combination with other endocrine agents［selective estrogenreceptor degraders（SERDs）and selective estrogen receptor covalent antagonists（SERCAs）］，continuation use of CDK4/6 inhibitors（cross-line therapy and new-generation inhibitors），switching to alternative targeted therapies［PI3K/AKT/mTOR pathway inhibitors，antibody-drug conjugate（ADC），poly ADP-ribose polymerase（PARP）inhibitors，histone deacetylase（HDAC）inhibitors］andchemotherapy. Clinical practice requires tailoring precision treatment strategies based on individual patient characteristics. This article systematically reviews the research progress on the resistance mechanisms of CDK4/6 inhibitors in breast cancer and correspondingtherapeutic strategies.