基于肺肠轴探讨肺癌免疫治疗的机遇与挑战

Exploring the Opportunities and Challenges of Lung Cancer Immunotherapy through the Lung-Gut Axis

摘要: 肺癌是全球癌症相关死亡的主要原因。免疫检查点抑制剂(Immune Checkpoint Inhibitors, ICIs)显著改善了部分肺癌患者的预后，但其在应用时仍存在人群应答差异，原发性和获得性耐药以及免疫相关不良事件(immune-related Adverse Events, irAEs)等情况限制其临床获益。本文围绕肺肠轴的相关机制，综述肠道微生物及其代谢产物参与全身免疫调节和肺部肿瘤免疫微环境重塑的可能机制，并总结其在疗效预测和微生态干预中的研究进展。现有证据提示，肠道菌群多样性及部分菌群与ICIs疗效相关，肠道微生物及其代谢产物(如短链脂肪酸、胆汁酸)通过调控宿主炎症通路、黏膜免疫及免疫细胞归巢，远程重塑肺部免疫微环境；其中，双歧杆菌等有利菌群可增强免疫疗效，而具核梭杆菌等不利菌群则促进耐药发生。通过粪菌移植、益生菌/后生元、中医药及工程菌等“由肠治肺”的干预策略在增敏免疫治疗方面显示出巨大潜力。未来应通过标准化，多中心，前瞻性研究整合宏基因组，代谢组学等研究手段，寻找可重复的生物标志物和干预靶点，以推动肺肠轴研究向精准免疫治疗转化。

Abstract: Lung cancer is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved outcomes in a subset of patients with lung cancer, their clinical benefits remain limited by interindividual variability in treatment response, primary and acquired resistance, and immune-related adverse events (irAEs). Focusing on the underlying mechanisms of the lung-gut axis, this review summarizes the potential mechanisms by which the gut microbiota and its metabolites contribute to systemic immune regulation and the remodeling of the pulmonary tumor immune microenvironment, and discusses recent advances in their application to therapeutic response prediction and microbiota-based interventions. Current evidence suggests that gut microbial diversity and specific bacterial taxa are associated with the efficacy of ICIs. Gut microorganisms and their metabolites, including short-chain fatty acids and bile acids, may remotely remodel the pulmonary immune microenvironment by regulating host inflammatory pathways, mucosal immunity, and immune-cell homing. Beneficial taxa, such as Bifidobacterium spp., may enhance the efficacy of immunotherapy, whereas unfavorable taxa, such as Fusobacterium nucleatum, may promote the development of treatment resistance. “Treating the gut to benefit the lung” strategies—including fecal microbiota transplantation, probiotics/postbiotics, traditional Chinese medicine, and engineered bacteria—have demonstrated considerable potential for sensitizing tumors to immunotherapy. In the future, standardized, multicenter, prospective studies should integrate metagenomics, metabolomics, and other multi-omics approaches to identify reproducible biomarkers and therapeutic targets, thereby facilitating the translation of lung-gut axis research into precision immunotherapy.