Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming.

中文翻译：

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用于癌症免疫治疗的基于合成 RNA 的免疫调节基因电路。

尽管在多项临床试验中取得了成功，但癌症免疫疗法仍然受到可靶向肿瘤特异性抗原的稀有、肿瘤介导的免疫抑制以及强效免疫调节剂的全身递送引发的毒性的限制。在这里，我们提出了一个概念验证的免疫调节基因电路平台，该平台能够实现免疫刺激剂的肿瘤特异性表达，这有可能克服这些限制。我们的设计包括从头合成癌症特异性启动子，以及为了增强特异性，基于 RNA 的 AND 门，仅当两个启动子相互活跃时才产生组合免疫调节输出。这些输出包括免疫原性细胞表面蛋白、细胞因子、趋化因子和检查点抑制剂抗体。在体外，这些电路触发了 T 细胞介导的选择性杀伤癌细胞，但不杀伤正常细胞。在体内功效测定中，慢病毒回路递送介导显着的肿瘤减少和延长的小鼠存活。我们的设计可以适应驱动额外的免疫调节剂，感知其他癌症，并可能治疗需要精确免疫编程的其他疾病。