ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1570040

This article is part of the Research TopicTargeting Cell Death Pathways for Enhanced Cancer Immunotherapy: Specific Involve in Necroptosis, Pyroptosis, Ferroptosis, Cuproptosis, Autophagy, Apoptosis, and ICD ResearchView all 10 articles

CDK2 Inhibition Sensitizes Anthracycline-Induced Immunogenic Cell Death and Enhances Anti-PD-1 Therapy Authors and affiliations

Provisionally accepted
Yu ChenYu Chen1Wancheng LiuWancheng Liu2Qiaomei caiQiaomei cai3Chaohu PanChaohu Pan4Zhenghao YinZhenghao Yin5Yijiao TangYijiao Tang5Zhixu HeZhixu He5Genhong ChengGenhong Cheng6*Liping ShuLiping Shu5*
  • 1Affiliated Hospital of Guizhou Medical University, Guiyang, China
  • 2Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China
  • 3Tianjin Medical University Cancer Institute and Hospital, Tianjin, Tianjin, China
  • 4Shenzhen Third People’s Hospital, Shenzhen, Guangdong Province, China
  • 5Guizhou Medical University, Guiyang, Guizhou Province, China
  • 6Immunology & Molecular Genetics, University of California, Los Angeles, United States

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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. We found that mice bearing Cdk2 -/- cancer cells exhibit slower tumor growth than WT cells after anthracycline analogue MTX (mitoxantrone) treatment, and this phenomenon is dependent on the immune system. Our findings reveal that the increased infiltration of CD8 + and CD11c + immune cells in Cdk2 -/-tumor tissues suggest an enhanced local immune response responding to MTX. 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. 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: Immunogenic cell death, CDK2, Anti-PD-1 Therapy, type-1 interferon response, MTX (mitoxantrone)

Received: 02 Feb 2025; Accepted: 05 May 2025.

Copyright: © 2025 Chen, Liu, cai, Pan, Yin, Tang, He, Cheng and Shu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Genhong Cheng, Immunology & Molecular Genetics, University of California, Los Angeles, United States
Liping Shu, Guizhou Medical University, Guiyang, 550025, Guizhou Province, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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