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CDK4/6 Inhibition Induces CD8+ T Cell Antitumor Immunity via MIF-Induced Functional Orchestration of Tumor-Associated

Lin He1,2,3,4,5, Yuzhong Peng1,2,3, Lat-Lun Leong6

  • 1Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 13, 2025
PubMed

Insights

Cyclin-dependent kinase 4 and 6 inhibition enhances breast cancer immunity by reprogramming macrophages. This reprogramming boosts CD8+ T cell activity, overcoming the immunosuppressive tumor microenvironment.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Cyclin-dependent kinases 4 and 6 (CDK4/6) control cell cycle G1 to S phase progression.
  • CDK4/6 inhibition (CDK4/6i) has shown potential in enhancing antitumor immunity, specifically increasing CD8+ T cell infiltration, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which CDK4/6i enhances intratumoral CD8+ T cell infiltration in breast tumors.
  • To investigate the role of tumor-associated macrophages (TAMs) in mediating the interaction between CDK4/6i and CD8+ T cells.

Main Methods:

  • Investigated the impact of CDK4/6i on TAM polarization and function.
  • Analyzed the role of macrophage migration inhibitory factor (MIF) and the MIF-CD44/CD74 axis in mediating TAM reprogramming.
  • Assessed the effect of CDK4/6i-trained M1 TAMs on CD8+ T cell activation and proliferation.
  • Evaluated the efficacy of CDK4/6i-trained M1 TAM supernatant therapy in combination with PD-1 blockade in preclinical breast cancer models.

Main Results:

  • CDK4/6i promotes M1 TAM accumulation and M2 to M1 polarization through enhanced MIF-CD44/CD74 interactions between tumor cells and macrophages.
  • CDK4/6i upregulates tumor cell MIF secretion via the HIF-1α pathway.
  • CDK4/6i-trained M1 TAMs enhance CD8+ T cell populations and activation via MHC-I antigen presentation.
  • Inhibition of MIF or Mif loss in tumor cells abrogates the immunostimulatory effects of CDK4/6i.
  • CDK4/6i-trained M1 TAM supernatant therapy overcomes tumor immunosuppression and synergizes with low-dose PD-1 blockade.

Conclusions:

  • CDK4/6i enhances antitumor immunity in breast cancer by functionally reprogramming TAMs towards an M1 phenotype.
  • The MIF-CD44/CD74 axis and HIF-1α pathway are critical mediators of CDK4/6i-induced TAM reprogramming and subsequent CD8+ T cell activation.
  • Targeting TAMs with CDK4/6i-trained M1 TAM supernatant offers a promising strategy to overcome the immunosuppressive tumor microenvironment and improve responses to immunotherapy.
Keywords:
CD8+ T cellCDK4/6 inhibitorcell–cell communicationtumor immune microenvironmenttumor‐associated macrophage

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