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CDK10 suppresses nucleic acid sensors-mediated antitumor immunity


Gaoshan Xu, Fusheng Guo, Chuan He, Xiyong Wang, Bolin Xiang, Lifang Fan, Baoxiang Chen, Jiakun Peng, Yishuang Sun, Jie Shi, Xixin Xing, Yingmeng Yao, Panpan Dai, Haiou Li, Wenjun Xiong, Hudan Liu, Rui Xiao, Guoliang Qing, Congqing Jiang, Baishan Jiang, Xiaoguang Lei* & Jinfang Zhang*
Nature Cancer (2026)
https://doi.org/10.1038/s43018-025-01100-3

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.

Gaoshan Xu, Fusheng Guo, Chuan He, Xiyong Wang, Bolin Xiang, Lifang Fan, Baoxiang Chen, Jiakun Peng, Yishuang Sun, Jie Shi, Xixin Xing, Yingmeng Yao, Panpan Dai, Haiou Li, Wenjun Xiong, Hudan Liu, Rui Xiao, Guoliang Qing, Congqing Jiang, Baishan Jiang, Xiaoguang Lei* & Jinfang Zhang*
 
Nature Cancer (2026)
https://doi.org/10.1038/s43018-025-01100-3
 
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.