The efficacy of immunotherapy in prostate cancer patients is limited due to the "cold" tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis is involved in innate immunity and has been increasingly recognized as a candidate target for cancer immunotherapy. Here, we found that treatment with CDK4/6 inhibitors stimulates the STING pathway and enhances the antitumor effect of STING agonists in prostate cancer. Mechanistically, CDK4/6 phosphorylated TBK1 at S527 to inactivate the STING signaling pathway independent of RB1 in prostate cancer cells. CDK4/6-mediated phosphorylation of RB1 at S249/T252 also induced the interaction of RB1 with TBK1 to diminish the phosphorylation of TBK1 at S172, which suppressed STING pathway activation. Overall, this study showed that CDK4/6 suppresses the STING pathway through RB1-dependent and RB1-independent pathways, indicating that CDK4/6 inhibition could be a potential strategy to overcome immunosuppression in prostate cancer.
Cancer research. 2024 Jun 11 [Epub ahead of print]
Wei Li, Feng Guo, Ruijiang Zeng, Huaiyuan Liang, Yinhuai Wang, Wei Xiong, Heshui Wu, Chunguang Yang, Xin Jin
Second Xiangya Hospital of Central South University, Changsha, China., Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Second Xiangya Hospital of Central South University, changsha, China., Second Xiangya Hospital of Central South University, China., Tongji Hospital, Wuhan, China.