Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of CD4 + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors.

中文翻译：

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Stat3致癌基因成瘾的阻断可诱导细胞衰老，并揭示出适合癌症免疫疗法的非细胞自主活性。

Stat3在几种肿瘤类型中被组成性激活，并且在维持其恶性表型和免疫抑制中起重要作用。为了利用Stat3靶向的有希望的抗肿瘤活性，了解Stat3调节细胞自主过程和非自主过程的机制至关重要。在这里，我们证明了关闭不同癌细胞类型中的Stat3组成型激活会诱导衰老，从而揭示其Stat3成瘾。利用Stat3沉默（SASP-siStat3）诱导的衰老相关分泌表型（SASP），我们设计了一种免疫疗法。SASP-siStat3免疫疗法的使用可强烈抑制与CD4 + T和NK细胞活化相关的三阴性乳腺癌和黑色素瘤的生长。将该免疫疗法与抗PD-1抗体联合使用可提高荷黑素瘤小鼠的存活率。SASP组件的特征表明，由环状GMP-AMP合酶DNA传感途径的激活触发的I型IFN相关介体对其免疫监视活性很重要。总的来说，我们的发现提供了证据，即服用SASP-siStat3或低剂量的Stat3阻断剂将使Stat3上瘾的肿瘤患者受益，从而释放出抗肿瘤免疫反应并提高免疫检查点抑制剂的有效性。对于其免疫监视活性很重要。总的来说，我们的发现提供了证据，即服用SASP-siStat3或低剂量的Stat3阻断剂将使Stat3上瘾的肿瘤患者受益，从而释放出抗肿瘤免疫反应并提高免疫检查点抑制剂的有效性。对于其免疫监视活性很重要。总的来说，我们的发现提供了证据，即服用SASP-siStat3或低剂量的Stat3阻断剂将使Stat3上瘾的肿瘤患者受益，从而释放出抗肿瘤免疫反应并提高免疫检查点抑制剂的有效性。