Department of Pathology, School of Clinical Medicine, and.
State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
JCI Insight. 2024 Nov 22;9(22):e170532. doi: 10.1172/jci.insight.170532.
Cell cycle inhibitors have a long history as cancer treatment. Here, we report that these inhibitors combated cancer partially via the stimulator of IFN genes (STING) signaling pathway. We demonstrated that paclitaxel (microtubule stabilizer), palbociclib (cyclin-dependent kinase 4/6 inhibitor), and AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anticancer functions beyond arresting the cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic hepatocellular carcinoma (HCC) cells more sensitive to the antimitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment with cell cycle inhibitors, especially paclitaxel, extended survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that paclitaxel suppressed Sting wild-type HCC more effectively than Sting-KO HCC, suggesting that STING might contribute to the antitumor effects of paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.
细胞周期抑制剂作为癌症治疗已有很长的历史。在这里，我们报告这些抑制剂通过干扰素基因刺激物 (STING) 信号通路部分对抗癌症。我们证明紫杉醇（微管稳定剂）、帕博西尼（细胞周期蛋白依赖性激酶 4/6 抑制剂）以及 AZD1152 和 GSK1070916（极光激酶 B 抑制剂）具有超出细胞周期阻滞的抗癌作用。它们一致地导致细胞质 DNA 积累和 DNA 损伤，这无意中触发细胞质 DNA 传感器 DEAD 框螺旋酶 41（DDX41）并激活 STING 以分泌促炎衰老相关分泌表型因子 (SASPs)。有趣的是，我们发现 DDX41 是 HIF 的转录靶标。缺氧通过 HIF-1 诱导 DDX41 的表达，使缺氧肝细胞癌 (HCC) 细胞对 STING 激活和 SASP 产生中的抗有丝分裂剂更敏感。SASPs 触发肿瘤中的免疫细胞浸润以清除癌症。当与抗 PD-1 联合使用时，细胞周期抑制剂（特别是紫杉醇）的治疗通过扰乱小鼠 HCC 生长来延长生存期。我们观察到紫杉醇抑制 Sting 野生型 HCC 比 Sting-KO HCC 更有效，这表明 STING 可能有助于紫杉醇的抗肿瘤作用。我们的研究揭示了细胞周期抑制剂的免疫介导的肿瘤抑制特性，并提出了联合免疫治疗作为一种潜在的治疗方法。
