Effect of CDK4/6 Inhibitors on Tumor Immune Microenvironment

Immunol Invest. 2024 Apr;53(3):437-449. doi: 10.1080/08820139.2024.2304565. Epub 2024 Feb 5.


Cancer is an abnormal proliferation of cells that is stimulated by cyclin-dependent kinases (CDKs) and defective cell cycle regulation. The essential agent that drive the cell cycle, CDK4/6, would be activated by proliferative signals. Activated CDK4/6 results in the phosphorylation of the neuroblastoma protein (RB) and the release of the transcription factor E2F, which promotes the cell cycle progression. CDK4/6 inhibitor (CDK4/6i) has been currently a research focus, which inhibits the CDK4/6-RB-E2F axis, thereby reducing the cell cycle transition from G1 to S phase and mediating the cell cycle arrest. This action helps achieve an anti-tumor effect. Recent research has demonstrated that CDK4/6i, in addition to contributing to cell cycle arrest, is also essential for the interaction between the tumor cells and the host immune system, i.e., activating the immune system, strengthening the tumor antigen presentation, and reducing the number of regulatory T cells (Treg). Additionally, CDK4/6i would elevate the level of PD-L1, an immunosuppressive factor, in tumor cells, and CDK4/6i in combination with anti-PD-L1 therapy would more effectively reduce the tumor growth. Our results showed that CDK4/6i caused autophagy and senescence in tumor cells. Herein, the impact of CDK4/6i on the immune microenvironment of malignant tumors was mainly focused, as well as their interaction with immune checkpoint inhibitors in affecting anti-tumor immunity.

Keywords: Cell cycle; combination therapy; cyclin-dependent kinase 4/6 inhibitor; immune; tumor microenvironment.

Publication types

  • Review

MeSH terms

  • Cell Cycle
  • Cell Cycle Checkpoints
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 4 / pharmacology
  • Cyclin-Dependent Kinase 6* / metabolism
  • Cyclin-Dependent Kinase 6* / pharmacology
  • Humans
  • Neoplasms* / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Tumor Microenvironment


  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Protein Kinase Inhibitors
  • CDK4 protein, human