胃肠道恶性肿瘤中的NLRP3炎性小体：分子机制、调控网络和治疗机会

摘要(中文译文)

NLRP3炎症小体是先天免疫系统中关键的炎症感知平台。它整合病原体相关分子模式、损伤相关分子模式以及多种细胞应激信号。一旦被激活，它促进caspase-1活化、IL-1β和IL-18的成熟与释放，以及gasdermin D介导的细胞焦亡。通过这些过程，NLRP3炎症小体参与炎症反应和组织稳态的维持。越来越多的证据表明，NLRP3炎症小体在胃肠道恶性肿瘤的发生和进展中发挥关键而复杂的作用。在食管癌、胃癌和结直肠癌中，NLRP3活性可受微生物感染、胆汁酸刺激、环境致癌物、肠道菌群失调、代谢异常、线粒体功能障碍、活性氧蓄积以及治疗诱导的应激等因素调控。持续或异常的NLRP3激活可能促进慢性炎症、上皮屏障破坏、IL-1β介导的髓系细胞募集、免疫抑制性微环境形成、肿瘤侵袭和转移以及治疗耐药。相反，在特定治疗条件下，肿瘤细胞中NLRP3介导的细胞焦亡可增强抗原释放、激活抗肿瘤免疫，并提高化疗、放疗和免疫检查点抑制剂的疗效。因此，NLRP3炎症小体在胃肠道肿瘤中的功能高度依赖于细胞类型、疾病阶段、炎症强度、免疫组成和治疗背景。本综述总结了NLRP3炎症小体激活的分子机制、其在胃肠道恶性肿瘤中的促瘤和抑瘤作用、其与免疫检查点抑制剂反应的关系，以及靶向该通路的新兴治疗策略。NLRP3炎症小体在胃肠道恶性肿瘤中并非单纯的促瘤或抑瘤因子，其生物学效应具有高度背景依赖性。精准调控NLRP3而非简单的抑制或激活，可能为胃肠道肿瘤的个体化治疗提供新机遇。未来研究应明确NLRP3信号的细胞来源、激活状态、下游效应谱和免疫背景，以指导合理的治疗应用。

Abstract

The NLRP3 inflammasome is a key inflammatory sensing platform in the innate immune system. It integrates pathogen-associated molecular patterns, damage-associated molecular patterns, and diverse cellular stress signals. Once activated, it promotes caspase-1 activation, maturation and release of IL-1β and IL-18, and gasdermin D-mediated pyroptosis. Through these processes, the NLRP3 inflammasome contributes to inflammatory responses and the maintenance of tissue homeostasis. Increasing evidence has shown that the NLRP3 inflammasome plays a critical but complex role in the initiation and progression of gastrointestinal malignancies. In esophageal cancer, gastric cancer, and colorectal cancer, NLRP3 activity can be regulated by microbial infection, bile acid stimulation, environmental carcinogens, gut dysbiosis, metabolic abnormalities, mitochondrial dysfunction, reactive oxygen species accumulation, and treatment-induced stress. Sustained or aberrant NLRP3 activation may promote chronic inflammation, epithelial barrier disruption, IL-1β-mediated myeloid cell recruitment, immunosuppressive microenvironment formation, tumor invasion and metastasis, and therapeutic resistance. In contrast, under specific therapeutic conditions, NLRP3-mediated pyroptosis in tumor cells can enhance antigen release, activate antitumor immunity, and improve the efficacy of chemotherapy, radiotherapy, and immune checkpoint inhibitors. Therefore, the function of the NLRP3 inflammasome in gastrointestinal tumors is highly dependent on cell type, disease stage, inflammatory intensity, immune composition, and treatment context. This review summarizes the molecular mechanisms of NLRP3 inflammasome activation, its tumor-promoting and tumor-suppressive roles in gastrointestinal malignancies, its relationship with immune checkpoint inhibitor response, and emerging therapeutic strategies targeting this pathway. The NLRP3 inflammasome is not simply a tumor-promoting or tumor-suppressive factor in gastrointestinal malignancies. Instead, its biological effects are highly context dependent. Precise modulation of NLRP3, rather than simple inhibition or activation, may provide new opportunities for individualized treatment of gastrointestinal cancers. Future studies should define the cellular source, activation state, downstream effector profile, and immune context of NLRP3 signaling to guide rational therapeutic application.

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