2. Academic Validation
  3. CDK10 suppresses nucleic acid sensors-mediated antitumor immunity

CDK10 suppresses nucleic acid sensors-mediated antitumor immunity

  • Nat Cancer. 2026 Feb;7(2):283-303. doi: 10.1038/s43018-025-01100-3.
Gaoshan Xu # 1 2,  Fusheng Guo # 3 4,  Chuan He # 1 2,  Xiyong Wang # 1 2,  Bolin Xiang 1 2,  Lifang Fan 5,  Baoxiang Chen 6,  Jiakun Peng 7,  Yishuang Sun 1 2 5,  Jie Shi 1 2,  Xixin Xing 1 2,  Yingmeng Yao 1 2,  Panpan Dai 1,  Haiou Li 8,  Wenjun Xiong 1 2,  Hudan Liu 1 2,  Rui Xiao 7,  Guoliang Qing 1 2,  Congqing Jiang 6,  Baishan Jiang 1,  Xiaoguang Lei 9 10 11,  Jinfang Zhang 12 13
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 2 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
  • 3 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 4 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 5 Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 6 Department of Colorectal and Anal Surgery, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 7 Department of Hematology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 8 Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 9 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [email protected].
  • 10 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
  • 11 Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. [email protected].
  • 12 Department of Radiation and Medical Oncology, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. [email protected].
  • 13 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 41507536 DOI: 10.1038/s43018-025-01100-3
Abstract

Cancer immunotherapies have revolutionized Cancer treatment, yet many patients fail to respond. Activating innate immunity offers a promising approach to enhance therapeutic efficacy, but the signaling kinases directly regulating this process to boost antitumor responses remain elusive. Here we conduct an in vivo kinome CRISPR screen and identify CDK10 as a key suppressor of tumor immune surveillance. Mechanistically, CDK10 phosphorylates DNMT1 and RAP80 to reduce the accumulation of double-stranded RNA and R-loops, which alleviates the activation of innate immune pathways mediated by MDA5 and cGAS. Kinase inhibitor screens identify NVP-AST487 and ponatinib as selective CDK10 inhibitors. Both genetic and pharmacological inhibition of CDK10 activates MDA5 and cGAS pathways, fostering an immunoactive tumor microenvironment that enhances Cancer Immunotherapy in multiple mouse tumor models. Clinically, low CDK10 expression in tumors correlates with better immunotherapy responses. These findings establish CDK10 as a pivotal modulator of tumor immunity and a potential therapeutic target.

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