The efficacy of immunotherapy in patients with prostate cancer 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. Significance: Inhibiting CDK4/6 activates STING-TBK1-IRF3 signaling in prostate cancer by regulating TBK1 phosphorylation, suggesting that the combination of CDK4/6 inhibitors and STING agonists could be an effective approach to stimulate innate immunity.

中文翻译：

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CDK4/6 改变 TBK1 磷酸化以抑制前列腺癌中的 STING 信号通路。


由于“冷”的肿瘤微环境和新抗原的缺乏，免疫疗法对前列腺癌患者的疗效受到限制。 STING-TBK1-IRF3 信号轴参与先天免疫，并越来越多地被认为是癌症免疫治疗的候选靶点。在这里，我们发现 CDK4/6 抑制剂治疗可刺激 STING 通路并增强 STING 激动剂在前列腺癌中的抗肿瘤作用。从机制上讲，CDK4/6 在 S527 位点磷酸化 TBK1，从而使前列腺癌细胞中不依赖于 RB1 的 STING 信号通路失活。 CDK4/6 介导的 RB1 在 S249/T252 处的磷酸化也诱导 RB1 与 TBK1 的相互作用，从而减少 TBK1 在 S172 处的磷酸化，从而抑制 STING 通路激活。总体而言，本研究表明 CDK4/6 通过 RB1 依赖性和 RB1 独立途径抑制 STING 途径，表明 CDK4/6 抑制可能是克服前列腺癌免疫抑制的潜在策略。意义：抑制CDK4/6通过调节TBK1磷酸化激活前列腺癌中的STING-TBK1-IRF3信号传导，表明CDK4/6抑制剂和STING激动剂的组合可能是刺激先天免疫的有效方法。