2. Academic Validation
  3. CDK2 inhibition sensitizes anthracycline-induced immunogenic cell death and enhances the efficacy of anti-PD-1 therapy

CDK2 inhibition sensitizes anthracycline-induced immunogenic cell death and enhances the efficacy of anti-PD-1 therapy

  • Front Immunol. 2025 Jun 10:16:1570040. doi: 10.3389/fimmu.2025.1570040.
Yu Chen # 1,  Wancheng Liu # 2,  Qiaomei Cai # 3,  Chaohu Pan 4,  Zhenghao Yin 1,  Yijiao Tang 1,  Zhixu He 5,  Genhong Cheng 6,  Liping Shu 1 5
Affiliations

Affiliations

  • 1 School of Basic Medicine, Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, China.
  • 2 Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, China.
  • 3 Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
  • 4 National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
  • 5 Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, China.
  • 6 Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
  • # Contributed equally.
PMID: 40557162 DOI: 10.3389/fimmu.2025.1570040
Abstract

Introduction: CDK2 (Cyclin-dependent kinase 2) is an oncogenic cyclin-dependent kinase with potent mitogenic and immunosuppressive functions. Despite extensive research on CDK2 inhibitors, the lack of selectivity has made it unclear whether CDK2 inhibition specifically facilitate immunogenic cell death.

Methods: We used CRISPR-Cas9 system to generate CDK2-/- MCA205 cells. Tumor cells were inoculated subcutaneously into mice while administering MTX (mitoxantrone) or anti-PD-1 antibodies treatment to observe tumor growth curves. Next, immune cell infiltration in tumor microenvironment was detected by immunofluorescence. Furthermore, Apoptosis pathway was evaluated by flow cytometry and western blot. The hallmarks of immunogenic cell death were detected by flow cytometry, ELISA or qRT-PCR.

Results: We found that mice bearing CDK2-/- Cancer cells exhibit slower tumor growth than WT cells after anthracycline analogue MTX treatment, and this phenomenon is dependent on the immune system. Furthermore, our data exhibits that CDK2-/- Cancer cells treated with MTX trigger a more robust immunostimulatory responses than WT cells, including Apoptosis stress response, surface calreticulin expression, endoplasmic reticulum stress response, HMGB1 (High Mobility Group Box 1) release, and type-1 interferon response.

Discussion: This study not only suggests that CDK2 inhibition improves the outcome of chemotherapy by enhancing the type-1 interferon response but also investigates the synergistic effects of CDK2 inhibition with MTX or anti-PD-1 antibodies in immunocompetent mice.

Keywords

CDK2; MTX; anti-PD-1 therapy; immunogenic cell death; type-1 interferon response.

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