STING (stimulator of interferon genes) signaling pathway has attracted considerable attention in cancer immunotherapy due to its capacity to boost vigorous antitumor immunity. However, the shortage of effective STING agonists limits the promotion of STING pathway in cancer treatment. Herein, we present an approach for in situ activation of STING pathway with nanoparticles delivered DNA-targeting chemo agents, based on the understanding that cytosol DNA is a pre-requisite for STING pathway activation. Through in vitro screening among several DNA-targeting chemo agents, we identified 7-ethyl-10-hydroxycamptothecin (SN38) as the most potent drug for stimulating interferon (IFN)-β secretion and proved that this process is mediated by the passage of DNA-containing exosomes from treated tumor cells to bone marrow-derived dendritic cells (BMDCs) and subsequent activation of the STING pathway. Furthermore, we designed a polymeric-SN38 conjugate that could self-assemble into nanoparticles (SN38-NPs) for in vivo application. The SN38-NPs formulation reduced toxicity of free SN38, effectively stimulated the activation of STING pathway in E0771 tumors, and resulted in a tumor suppression rate (TSR%) of 82.6%. Our results revealed a new mechanism of SN38 in cancer treatment and should inspire using more DNA-targeting agents, especially in nanoformulation, for activating STING pathway and cancer chemoimmunotherapy.

STING（干扰素基因的刺激物）信号传导途径因其具有增强抗肿瘤免疫力的能力而备受关注。然而，有效的STING激动剂的缺乏限制了在癌症治疗中STING途径的促进。在本文中，我们基于细胞质DNA是STING途径激活的前提条件，提出了一种利用纳米颗粒递送的DNA靶向化学剂原位激活STING途径的方法。通过体外在几种靶向DNA的化学药物中进行筛选，我们确定7-乙基-10-羟基喜树碱（SN38）是刺激干扰素（IFN）-β分泌的最有效药物，并证明此过程是由含DNA的外来体介导的从治疗的肿瘤细胞到骨髓源性树突状细胞（BMDC），然后激活STING通路。此外，我们设计了一种聚合物-SN38共轭物，可以在体内自组装成纳米颗粒（SN38-NP）应用。SN38-NPs制剂降低了游离SN38的毒性，有效刺激了E0771肿瘤中STING途径的激活，导致抑瘤率（TSR％）为82.6％。我们的研究结果揭示了SN38在癌症治疗中的新机制，应该启发人们使用更多的DNA靶向剂，尤其是在纳米制剂中，以激活STING途径和癌症化学免疫疗法。