Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations, including cancer cells, with distinct cellular functions, such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here, using a polymeric STING-activating nanoparticle (PolySTING) with a shock-and-lock dual activation mechanism, we show that conventional type 1 dendritic cells (cDC1s) are essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells ( Tmem173 −/− ) is important for antitumor efficacy. Specific depletion of cDC1 ( Batf3 −/− ) or STING deficiency in cDC1 ( XCR1 cre STING fl/fl ) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wild-type cDC1 in Batf3 −/− mice restored antitumor efficacy, whereas transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wild-type but not Batf3 −/− mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival. Furthermore, STING-cDC1 signature was increased after neoadjuvant pembrolizumab therapy in patients with non–small cell lung cancer. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.

中文翻译：

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I 型树突状细胞的 STING 许可增强抗肿瘤免疫力

干扰素基因刺激物 (STING) 是一种免疫衔接蛋白，可感知环 GMP-AMP，以响应自身或微生物胞质 DNA 作为危险信号。STING 在包括癌细胞在内的多种细胞群中普遍表达，具有不同的细胞功能，例如激活 I 型干扰素、诱导自噬或触发细胞凋亡。目前尚不清楚免疫细胞、基质细胞或癌细胞是否以及哪些亚群对于 STING 介导的抗肿瘤免疫特别重要。在这里，我们使用具有休克和锁定双重激活机制的聚合物 STING 激活纳米颗粒 (PolySTING)，表明传统 1 型树突状细胞 (cDC1) 对于 STING 介导的多种已建立和转移性小鼠肿瘤的排斥至关重要。STING 状态存在于宿主中，但不存在于癌细胞中（TMEM173 −/−）对于抗肿瘤功效很重要。cDC1 的特定消耗（蝙蝠f3 −/−）或 cDC1 中的 STING 缺陷（XCR1克里刺液量/液量 ）废除了PolySTING的功效，而其他骨髓细胞的耗竭几乎没有影响。野生型 cDC1 的过继转移蝙蝠f3 −/−小鼠恢复了抗肿瘤功效，而转移具有 STING 或 IRF3 缺陷的 cDC1 未能挽救小鼠。PolySTING 在野生型中诱导了特定的趋化因子特征，但没有蝙蝠f3 −/−老鼠。对切​​除肿瘤中 STING 激活的 cDC1 进行多重免疫组织化学分析与患者生存相关。此外，非小细胞肺癌患者接受派姆单抗新辅助治疗后，STING-cDC1 特征增加。因此，我们确定髓系细胞的一个子集对于 STING 介导的抗肿瘤免疫以及相关的预后生物标志物至关重要。