澳大利亚哈德逊医学研究所Daniel J. Gough团队近期取得重要工作进展，他们研究发现，STAT3-STING-IFN通路控制小细胞肺癌的转移扩散。相关研究成果2024年11月21日在线发表于《自然—免疫学》杂志上。

据介绍，小细胞肺癌（SCLC）是一种侵袭性神经内分泌肿瘤，其特征是转移潜能高，总生存率约为5%。转录因子信号转导和转录激活因子3（STAT3）在50%以上的肿瘤中过表达，包括SCLC，但其在SCLC发展和转移中的作用尚不清楚。

研究人员发现，虽然STAT3缺失限制了原发性肿瘤的生长，但矛盾的是，它通过促进免疫逃避来增强转移扩散。这是因为STAT3对于维持干扰素（IFN）基因的免疫传感器刺激因子（STING）至关重要。

没有STAT3，环腺苷酸-鸟苷酸合酶-STING通路是不活跃的，导致I型IFN分泌减少和IFN基因特征。重要的是，通过内源性STING的重新表达、IFN反应因子7的强制表达或重组I型IFN的给药恢复IFN信号传导，重建了抗肿瘤免疫，抑制了体内转移性SCLC。

总之，这些数据显示了增强先天免疫反应，以阻断转移性SCLC的潜力。

附：英文原文

Title: A STAT3–STING–IFN axis controls the metastatic spread of small cell lung cancer

Author: Guanizo, Aleks C., Luong, Quinton, Jayasekara, W. Samantha N., de Geus, Eveline D., Inampudi, Chaitanya, Xue, Vincent Senyang, Chen, Jasmine, de Weerd, Nicole A., Matthews, Antony Y., Gantier, Michael P., Balic, Jesse J., Arulananda, Surein, Garama, Daniel J., Hertzog, Paul J., Ganju, Vinod, Watkins, D. Neil, Cain, Jason E., Gough, Daniel J.

Issue&Volume: 2024-11-21

Abstract: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion. This occurs because STAT3 is crucial for maintaining the immune sensor stimulator of interferon (IFN) genes (STING). Without STAT3, the cyclic adenosine monophosphate–guanosine monophosphate synthase–STING pathway is inactive, resulting in decreased type I IFN secretion and an IFN gene signature. Importantly, restoration of IFN signaling through re-expression of endogenous STING, enforced expression of IFN response factor 7 or administration of recombinant type I IFN re-established antitumor immunity, inhibiting metastatic SCLC in vivo. These data show the potential of augmenting the innate immune response to block metastatic SCLC.

DOI: 10.1038/s41590-024-02014-5

Source: https://www.nature.com/articles/s41590-024-02014-5