An immunological mechanism of resistance to CDK4/6 inhibitors in HR+ breast cancer

Oncoimmunology. 2025 Dec;14(1):2520269. doi: 10.1080/2162402X.2025.2520269. Epub 2025 Jul 15.

Abstract

CDK4/6 inhibitors are central to the clinical management of HR+HER2- breast cancer. We have recently demonstrated that immunosuppressive, IL17-secreting γδ T cells recruited to the tumor microenvironment by a CCL2-dependent mechanism upon CDK4/6 inhibition can repolarize tumor-associated macrophages toward a CX3CR1+ phenotype associated with resistance to therapy.

Keywords: Circulating biomarker; TAMs; endocrine therapy; hypoxia; palbociclib; single-cell RNA sequencing.

Publication types

  • Editorial

MeSH terms

  • Animals
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / immunology
  • Breast Neoplasms* / pathology
  • Cyclin-Dependent Kinase 4* / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6* / antagonists & inhibitors
  • Drug Resistance, Neoplasm* / immunology
  • Erb-b2 Receptor Tyrosine Kinases / metabolism
  • Female
  • Humans
  • Intraepithelial Lymphocytes / immunology
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Receptors, Estrogen / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / immunology

Substances

  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Protein Kinase Inhibitors
  • Receptors, Estrogen
  • Erb-b2 Receptor Tyrosine Kinases
  • CDK4 protein, human
  • CDK6 protein, human