胃癌中cGAS-STING通路介导的免疫微环境重塑与治疗增敏

cGAS-STING Pathway-Mediated Immune Microenvironment Remodeling and Therapeutic Sensitization in Gastric Cancer

摘要: 胃癌是一种高度异质性的恶性肿瘤，晚期患者及免疫“冷”肿瘤亚型的治疗效果仍然有限。越来越多的研究表明，环鸟苷酸–腺苷酸合成酶–干扰素基因刺激蛋白通路，即cGAS-STING通路，是细胞质DNA感知的重要机制，能够将基因组不稳定性、线粒体DNA外泄、病毒感染以及治疗诱导的DNA损伤与先天免疫和适应性抗肿瘤免疫反应联系起来。该通路激活后，可促进I型干扰素产生、炎症因子释放、树突状细胞活化、细胞毒性T细胞募集以及巨噬细胞再极化，从而重塑胃癌免疫微环境。近期研究进一步提示，cGAS-STING通路失调与胃癌免疫逃逸、免疫检查点抑制剂反应不佳以及治疗抵抗密切相关，而重新激活该通路可能增强化疗、放疗、HER2靶向治疗、抗血管生成治疗及免疫治疗的疗效。本文拟系统总结cGAS-STING通路在胃癌中的分子基础，重点关注DNA损伤应答、肿瘤细胞内在调控因素以及肿瘤免疫微环境重塑机制；进一步讨论该通路在铂类化疗、放疗、抗体偶联药物、免疫检查点抑制剂、STING激动剂以及纳米递送系统等治疗模式中的增敏作用。最后，本文将分析当前研究面临的主要挑战，包括通路异质性、情境依赖性的促肿瘤效应、生物标志物筛选、药物递送限制及安全性问题。深入理解cGAS-STING通路在胃癌中的生物学作用，有望为建立生物标志物指导下的联合治疗策略、改善胃癌免疫治疗效果提供理论依据。

Abstract: Gastric cancer is a highly heterogeneous malignancy, and treatment efficacy stays limited for advanced‑stage patients and immune‑cold tumour subtypes. Growing studies have proven that the cyclic guanosine monophosphate‑adenosine monophosphate synthase‑stimulator of interferon genes (cGAS‑STING) pathway acts as a vital cytoplasmic DNA‑sensing mechanism. It connects genomic instability, mitochondrial DNA leakage, viral infection and therapy‑induced DNA damage with innate immunity as well as adaptive antitumour immune responses. Once activated, this pathway boosts type‑I interferon production, inflammatory‑factor secretion, dendritic‑cell activation, cytotoxic T‑cell recruitment and macrophage repolarisation, consequently remodelling the immune microenvironment of gastric cancer. Recent research further suggests that cGAS‑STING pathway dysfunction is closely associated with gastric‑cancer immune evasion, unsatisfactory responses to immune checkpoint inhibitors and therapeutic resistance. Re‑activating this pathway is able to improve the curative effect of chemotherapy, radiotherapy, HER2‑targeted therapy, anti‑angiogenic therapy and immunotherapy. This review intends to systematically conclude the molecular basis of the cGAS‑STING pathway in gastric cancer, focusing on DNA‑damage responses, intrinsic regulatory factors inside tumour cells and remodelling mechanisms of the tumour immune microenvironment. It further explores the sensitising effect of this pathway on multiple treatment schemes, including platinum‑based chemotherapy, radiotherapy, antibody‑drug conjugates, immune checkpoint inhibitors, STING agonists and nano‑delivery systems. In the end, this paper analyzes primary challenges in current investigations, covering pathway heterogeneity, context‑dependent tumour‑promoting effects, biomarker screening, drug‑delivery constraints and safety‑related problems. An in‑depth understanding of the biological functions of the cGAS‑STING pathway in gastric cancer is expected to provide theoretical support for developing biomarker‑guided combined therapeutic strategies and optimising the clinical outcomes of gastric‑cancer immunotherapy.