探索肠道-代谢物-免疫轴：增强免疫检查点抑制剂的疗效并减轻毒性

摘要(中文译文)

免疫检查点抑制剂（ICIs）通过阻断抑制性通路，尤其是程序性细胞死亡蛋白-1/程序性死亡配体1（PD-1/PD-L1）和细胞毒性T淋巴细胞相关抗原-4（CTLA-4）通路，从而重新激活宿主抗肿瘤免疫，彻底改变了肿瘤学格局。尽管这些药物已成为恶性肿瘤的一线标准疗法，但其临床效用仍然有限。患者间的治疗差异性本质上与肠道微生物组的组成和功能能力密切相关。其潜在机制似乎涉及微生物群与宿主免疫系统之间复杂的对话，其中微生物代谢物作为重塑肿瘤微环境的关键介质发挥作用。尽管取得了这些认识，但该领域的进展仍因研究队列和样本处理方法的异质性而受到制约，阻碍了可重复的个体化预测模型和临床干预策略的建立。因此，迫切需要系统性地阐明微生物组-代谢物-免疫轴，以优化ICI疗效与全身毒性之间的平衡。通过综合最新证据，本综述旨在突出特定菌群，包括、和，在ICI疗效中的关键作用。这些微生物及其代谢副产物通过增强树突状细胞交叉呈递和促进CD T细胞浸润来增强治疗反应，通常通过激活环鸟苷酸-腺苷酸合成酶-干扰素基因刺激因子或含核苷酸结合寡聚化结构域蛋白2信号通路实现。此外，这些微生物组分表现出保护心脏和结肠免受炎症和屏障破坏的能力，从而减轻免疫相关不良事件。尽管粪菌移植以及补充新一代封装益生菌、后生元或膳食纤维等干预措施在临床前和I期试验中已证明其可行性和安全性，但仍存在重大障碍。未来的进展需要大规模、多中心、标准化的纵向研究，整合宏基因组学和代谢组学，以构建稳健的跨癌种和跨人群预测模型。这种严格的验证将有助于开发精准的微生物干预措施，在最大化治疗获益的同时最小化不良反应的发生率。

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the oncological landscape by disrupting inhibitory pathways, notably programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathways, thereby reinvigorating host antitumor immunity. Although these agents have emerged as frontline standard therapies for malignancies, their clinical utility remains limited. Interpatient therapeutic variability is inextricably linked to the composition and functional capacity of the gut microbiome. The underlying mechanisms appear to involve a complex dialogue between the microbiota and host immune system, where microbial metabolites serve as critical mediators in remodeling the tumor microenvironment. Despite these insights, progression in the field remains constrained due to heterogeneity in study cohorts and sample-processing methodologies, hindering the establishment of reproducible individualized predictive models and clinical intervention strategies. Consequently, there is an urgent need to systematically delineate the microbiome-metabolite-immune axis to optimize the balance between ICI efficacy and systemic toxicity. By synthesizing the latest evidence, this review aimed to highlight the pivotal roles of specific taxa, including , , and , in ICI efficacy. These microbes and their metabolic byproducts potentiate therapeutic responses by enhancing dendritic cell cross-presentation and promoting CD T-cell infiltration, often via activation of the cyclic GMP-AMP synthase-stimulator of interferon genes or nucleotide-binding oligomerization domain-containing protein 2 signaling pathways. Furthermore, these microbial components demonstrate the ability to protect the heart and colon against inflammation and barrier disruption, thereby mitigating immune-related adverse events. Although the feasibility and safety of interventions such as fecal microbiota transplantation and supplementation with next-generation encapsulated probiotics, postbiotics, or dietary fiber have been demonstrated in preclinical and Phase I trials, substantial hurdles remain. Future progress requires large-scale, multicenter, standardized, longitudinal studies integrating metagenomics and metabolomics to construct robust cross-cancer and cross-population predictive models. Such rigorous validation would enable the development of precise microbial interventions that maximize therapeutic gains while minimizing the incidence of adverse reactions.

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