细胞周期抑制剂作为癌症治疗有着悠久的历史。在这里，我们报道这些抑制剂部分通过干扰素基因刺激剂 (STING) 信号通路对抗癌症。我们证明了紫杉醇（微管稳定剂）、Palbociclib（细胞周期蛋白依赖性激酶 4/6 抑制剂）、AZD1152 和 GSK1070916（极光激酶 B 抑制剂）除了阻止细胞周期外还具有抗癌功能。它们持续引起胞质 DNA 积累和 DNA 损伤，从而无意中触发胞质 DNA 传感器 DEAD-box 解旋酶 41 (DDX41) 并激活 STING 分泌促炎性衰老相关分泌表型因子 (SASP)。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 表达，使缺氧 HCC 细胞在 STING 激活和 SASP 产生中对抗有丝分裂剂更加敏感。 SASP 触发肿瘤中的免疫细胞浸润以清除癌症。细胞周期抑制剂（尤其是紫杉醇）与抗 PD-1 联合使用时，可通过干扰小鼠 HCC 生长来延长生存期。我们观察到紫杉醇抑制 STINGWT HCC 比 STINGKO HCC 更有效的趋势，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，并建议与免疫疗法联合治疗作为一种潜在的治疗方法。

Cell cycle inhibitors have a long history as cancer treatment. Here, we reported that these inhibitors combated cancer partially via Stimulator of IFN genes (STING) signaling pathway. We demonstrated that Paclitaxel (microtubule stabilizer), Palbociclib (cyclin dependent kinase 4/6 inhibitor), AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anti-cancer functions beyond arresting 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 HCC cells more sensitive to the anti-mitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment of cell cycle inhibitors, especially Paclitaxel, extends survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that Paclitaxel suppressed STINGWT HCC more effectively than STINGKO HCC, suggesting that STING might contribute to the anti-tumor 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.