激活STING双调控缺氧微环境和免疫应答抑制肝癌与结直肠癌的分子机制研究及STING激动剂联合治疗新方案探索

肝癌与结直肠癌严重威胁我国人民健康，因高发病率及死亡率在黑龙江省形势尤为严峻。干扰素基因刺激因子（STING）是机体对病原性DNA产生免疫应答的关键分子，我们前期已阐述其在泛癌中的表达及在免疫调控各环节中的作用，近期发现缺氧诱导STING失活会促进肿瘤生长，而其激活后的肿瘤生长抑制与免疫细胞浸润及HIF-1α下调相关。基于缺氧诱导的靶向治疗耐药可被VHL依赖的HIF-1α降解逆转的早期发现，结合高通量测序及生物信息学分析，我们提出“缺氧抑制STING促进肿瘤生长，而激活STING调控免疫的同时可通过STAT1/VHL下调HIF-1α抑制肝癌及结直肠癌生长并增敏靶向与抗PD-1治疗”的假设。拟通过患者肿瘤组织来源的PDC、PDX等模型探究STING对肿瘤发生的影响及机制，结合多组学标志物筛选及纳米载药技术，率先从STING双调控缺氧与免疫的角度为肝癌与结直肠癌的精准及联合治疗寻找新策略。

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are serious threats for the health of Chinese, and this threaten is particularly severe in Heilongjiang Province because of the high morbidity and mortality. Stimulator of interferon genes (STING), a vital molecule in organisms, was discovered in innate immunity responses reacting to pathogenic cytoplasmic DNA. We elaborated the expression level of STING in Pan-cancer and its impact in tumor immunoregulation. Recently, our group found that hypoxia-induced STING inactivation can promote tumor growth, however, the inhibition of tumor growth induced by activation of STING was significantly associated with anti-cancer immune cells infiltration and decreased HIF-1α expression. Given the previous research basis that hypoxia induced targeted therapy resistance can be reversed by VHL-dependent HIF-1α degradation and the analysis results of high-throughput sequencing and bioinformatics. We propose the hypothesis that the inhibition of STING induced by hypoxia promotes tumor growth and the activation of STING inhibits tumor growth and increases the sensitivity of tumor cells to targeted therapies and anti-PD-1 therapy via activation of anti-cancer immune responses, cooperating with the STAT1/VHL-dependent manner decreasing HIF-1α and alleviating intratumoral hypoxia in HCC and CRC. To verify this hypothesis, we will investigate the effect and mechanism of STING in tumor development by humanized mouse patient-derived cells (PDC) and patient-derived xenografts (PDX) models, combining with marker screening of transcriptome sequencing and nanomedicine technology. The project will provide a new therapeutic strategy of precise and combined treatment for human HCC and CRC from the perspective of activating STING to promote anti-cancer immune responses concurrently with down-regulating HIF-1α to alleviate hypoxia.