Targeting Cytosolic nucleic  Acid-Sensing Pathways for Cancer immunotherapies

Authors: Sandra Iurescia*†, Daniela Fioretti† and Monica Rinaldi*

The innate immune system provides the first line of defense against pathogen infection though also influences pathways involved in cancer immunosurveillance. The innate immune system relies on a limited set of germ line-encoded sensors termed pattern recognition receptors (PRRs), signaling proteins and immune response factors. Cytosolic receptors mediate recognition of danger damage-associated molecular patterns (DAMPs) signals. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Recent studies revealed that PRRs respond to nucleic acids (NA) released by dying, damaged, cancer cells, as danger DAMPs signals, and presence of signaling proteins across cancer types suggests that these signaling mechanisms may be involved in cancer biology. 

DAMPs play important roles in shaping adaptive immune responses through the activation of innate immune cells and immunological response to danger DAMPs signals is crucial for the host response to cancer and tumor rejection. Furthermore, PRRs mediate the response to NA in several vaccination strategies, including DNA immunization. As route of double-strand DNA intracellular entry, DNA immunization leads to expression of key components of cytosolic NA-sensing pathways. The involvement of NA-sensing mechanisms in the antitumor response makes these pathways attractive drug targets. 

Natural and synthetic agonists of NA-sensing pathways can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment and are being explored as promising adjuvants in cancer immunotherapies. 

In this minireview, we discuss how cGAS–STING and RIG-I–MAVS pathways have been targeted for cancer treatment in preclinical translational researches. In addition, we present a targeted selection of recent clinical trials employing agonists of cytosolic NA-sensing pathways showing how these pathways are currently being targeted for clinical application in oncology.

天然免疫系统提供了病原体注射后防御的第一道防线，并且会影响癌症免疫监察的通路。天然免疫系统依赖于一群高度保守的PRR模式识别受体，信号蛋白以及免疫调节因子。胞质受体介导了危险的DAMPs信号识别。一旦启动之后，这些sensor会启动很多信号串联系统，召集合成很多I型IFN以及炎症细胞因子。最近的研究表明，PRR对死亡、受伤或者癌症细胞的核酸的识别（统一作为DAMP），并且在多种癌症类型中都发现了这些信号蛋白，这表明细胞对核酸的识别可能与癌症生物学有关。

DAMP在特异性免疫系统的形成中非常重要，因为DAMP激活天然免疫细胞以及免疫应答对于宿主响应癌症和肿瘤排斥是飞叉哪个重要的。另外，PRR通过很多方式介导了核酸感知，包括DNA免疫。当双链DNA进入细胞后，DNA免疫就会启动关键的核酸感知信号通路中细胞因子的合成。这些信号通路在抗肿瘤应答中的作用使得它们可以被用来作为抗肿瘤药物的靶点。

核酸感知通路的天然及合成激动剂可以激发肿瘤细胞的细胞死亡，并招募免疫细胞比如DC，CD8+ T细胞以及NK细胞，进入肿瘤细胞微环境，后续作为癌症免疫治疗的可用细胞。

在这个简短review当众，我们会讨论cGAS-STING通路以及RIG-I-MAVS通路是如何被靶向用来治疗癌症。另外，我们还会展示一些其他的可以被靶向的通路。