cGAS-STING信号通路在妇科恶性肿瘤免疫微环境中的作用与治疗应用

doi:10.12280/gjfckx.20260130

摘要/Abstract

摘要：

环鸟苷酸-腺苷酸合酶（cyclic GMP-AMP synthase，cGAS）-干扰素基因刺激因子（stimulator of interferon gene，STING）信号通路是连接胞质DNA识别与抗肿瘤免疫激活的关键枢纽，在妇科恶性肿瘤免疫微环境重塑中具有重要作用。该通路在卵巢癌、宫颈癌和子宫内膜癌中的激活机制与生物学效应存在差异，既可增强抗原呈递，促进T细胞募集并激活抗肿瘤免疫，也可能诱导免疫抑制。BRCA/DNA聚合酶ε（DNA polymerase epsilon，POLE）相关改变、人乳头瘤病毒（human papilloma virus，HPV）蛋白干扰及微RNA（microRNA，miRNA）、表观遗传修饰、线粒体应激等共同参与其调控。围绕STING激动剂、多腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase，PARP]抑制剂、免疫检查点抑制剂及纳米递送等策略的研究显示出一定应用前景，但精准分层、局部递送、剂量控制及联合时序优化仍是临床转化的关键问题。

关键词: 生殖器肿瘤, 女（雌）性, 干扰素Ⅰ型, 肿瘤微环境, 抗肿瘤联合化疗方案, cGAS-STING信号通路

Abstract:

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway is a central hub connecting cytosolic DNA sensing to antitumor immune activation and plays a significant role in remodeling the immune microenvironment of gynecologic malignancies. The mechanisms of activation and biological effects of this pathway differ among ovarian cancer, cervical cancer, and endometrial cancer. It can enhance antigen presentation, promote T-cell recruitment, and activate antitumor immunity. But it may also induce immunosuppression. Its regulation involves BRCA/DNA polymerase epsilon (POLE)-related alterations, interference by human papilloma virus (HPV) proteins, as well as microRNAs (miRNAs), epigenetic modifications, mitochondrial stress, and others. Research focusing on strategies such as STING agonists, poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors, and nanodelivery systems shows promising application prospects. However, precise patient stratification, local delivery, dose control, and optimization of combination timing remain key challenges for clinical translation.

Key words: Genital neoplasms, female, Interferon typeⅠ, Tumor microenvironment, Antineoplastic combined chemotherapy protocols, cGAS-STING signaling pathway

吴雪丽, 张秀霞, 刘倩倩, 梁晓磊, 刘畅. cGAS-STING信号通路在妇科恶性肿瘤免疫微环境中的作用与治疗应用[J]. 国际妇产科学杂志, 2026, 53(4): 367-373.

WU Xue-li, ZHANG Xiu-xia, LIU Qian-qian, LIANG Xiao-lei, LIU Chang. The Role of the cGAS-STING Signaling Pathway in the Immune Microenvironment of Gynecologic Malignancies and Therapeutic Application[J]. Journal of International Obstetrics and Gynecology, 2026, 53(4): 367-373.

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药物名称	药物类型	适应证	组合/给药方式	临床试验分期	临床试验编号	状态	研究结果
MIW815（ADU- S100）	STING激动剂	晚期/转移性实体肿瘤或淋巴瘤	单药（肿瘤内注射）	Ⅰ期	NCT02675439	未提交注册平台结果	论文报告ORR为2.1%
MIW815（ADU- S100）	STING激动剂	晚期/转移性实体肿瘤或淋巴瘤	与PD-1检查点抑制剂 PDR001联合	Ⅰb期	NCT03172936	未提交注册平台结果	论文报告ORR为10.4%
MIW815（ADU- S100）	STING激动剂	复发/转移性头颈癌	与Pembrolizumab （Keytruda^®）联合	Ⅱ期	NCT03937141	已终止	官方记录16例入组，6例纳入ORR分析，其中1例CR、5例PR
MK-1454（Ulevostinag）	STING激动剂	晚期/转移性实体瘤或淋巴瘤	单药/与Pembrolizumab 联合	Ⅰ期	NCT03010176	完成	单药ORR为0%，联合ORR为24%（2018年阶段性结果）
E-7766	大环桥联型 STING激动剂	晚期实体瘤或淋巴瘤	肿瘤内注射	Ⅰ期	NCT04144140	已终止（非安全性原因）	ORR为0%；DCR为33.3%（8/24例SD）；常见治疗相关不良事件为寒战、发热和疲劳；3/23例在第1周期出现DLT
HG-381	非环二核苷酸类STING激动剂	晚期实体瘤	静脉给药	Ⅰ期	NCT04998422	招募中	尚无结果公布
GSK3745417	非环二核苷酸类STING激动剂	晚期实体瘤	静脉给药	Ⅰ期	NCT03843359	已终止（商业决策）	单药Q1W队列中2/24例出现DLT，Q3W队列中未出现DLT（0/7例）；与Dostarlimab联合时，GSK3745417采用Q1W（0/8例）或Q3W队列（0/13例）均未出现DLT；尚未报告ORR

药物名称	药物类型	适应证	组合/给药方式	临床试验分期	临床试验编号	状态	研究结果
MIW815（ADU- S100）	STING激动剂	晚期/转移性实体肿瘤或淋巴瘤	单药（肿瘤内注射）	Ⅰ期	NCT02675439	未提交注册平台结果	论文报告ORR为2.1%
MIW815（ADU- S100）	STING激动剂	晚期/转移性实体肿瘤或淋巴瘤	与PD-1检查点抑制剂 PDR001联合	Ⅰb期	NCT03172936	未提交注册平台结果	论文报告ORR为10.4%
MIW815（ADU- S100）	STING激动剂	复发/转移性头颈癌	与Pembrolizumab （Keytruda^®）联合	Ⅱ期	NCT03937141	已终止	官方记录16例入组，6例纳入ORR分析，其中1例CR、5例PR
MK-1454（Ulevostinag）	STING激动剂	晚期/转移性实体瘤或淋巴瘤	单药/与Pembrolizumab 联合	Ⅰ期	NCT03010176	完成	单药ORR为0%，联合ORR为24%（2018年阶段性结果）
E-7766	大环桥联型 STING激动剂	晚期实体瘤或淋巴瘤	肿瘤内注射	Ⅰ期	NCT04144140	已终止（非安全性原因）	ORR为0%；DCR为33.3%（8/24例SD）；常见治疗相关不良事件为寒战、发热和疲劳；3/23例在第1周期出现DLT
HG-381	非环二核苷酸类STING激动剂	晚期实体瘤	静脉给药	Ⅰ期	NCT04998422	招募中	尚无结果公布
GSK3745417	非环二核苷酸类STING激动剂	晚期实体瘤	静脉给药	Ⅰ期	NCT03843359	已终止（商业决策）	单药Q1W队列中2/24例出现DLT，Q3W队列中未出现DLT（0/7例）；与Dostarlimab联合时，GSK3745417采用Q1W（0/8例）或Q3W队列（0/13例）均未出现DLT；尚未报告ORR