《生命科学》 2026, 38(9): 1576-1593

肠道菌群在消化道肿瘤免疫治疗中的系统调控与精准干预

张一繁 , 薛 冉 , 沈 琳^*

北京大学肿瘤医院暨北京市肿瘤防治研究所消化肿瘤内科，恶性肿瘤发病机制及转化研究教育部重点实 验室，北京 100142

摘　要：

免疫检查点抑制剂的临床应用已重塑消化道肿瘤的治疗格局，但疗效异质性与耐药困境仍是制约其临床获益的核心瓶颈。肠道菌群作为人体最复杂的微生物生态系统，已成为调控宿主免疫与抗肿瘤治疗响应的核心枢纽。本文系统综述了肠道菌群在消化道肿瘤免疫治疗中的调控机制、临床证据及应用前景，重点阐述了菌群调控免疫治疗反应的分子机制、菌群相关生物标志物的临床价值、菌群调控化疗与放疗的免疫学启示，以及精准微生物干预策略的研究进展，以期为消化道肿瘤的精准治疗提供新思路。

通讯作者：沈 琳 , Email:shenlin@bjmu.edu.cn

Systemic regulation and precision intervention of the gut microbiome in immunotherapy for gastrointestinal cancers

ZHANG Yi-Fan , XUE Ran , SHEN Lin^*

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing100142, China

Abstract:

Gastrointestinal (GI) cancers impose an enormous global health burden, accounting for approximately one-quarter of all cancer diagnoses and one-third of cancer-related deaths worldwide. Although immune checkpoint inhibitors (ICIs) have reshaped the therapeutic landscape of GI malignancies, response heterogeneity, primary and acquired resistance—particularly in microsatellite-stable tumors—and immune-related adverse events (irAEs) remain formidable obstacles to durable clinical benefit. The purpose of this review is to synthesize current mechanistic insights, clinical evidence, and translational trategies concerning the gut microbiota as a systemic regulator of, and precision intervention target within, GI cancer immunotherapy. We first delineate the tumor-type-specific patterns of microbial dysbiosis across esophageal squamous cell carcinoma, gastric, colorectal, hepatocellular, and pancreatic cancers, highlighting the oral-esophageal-gut axis, the transition beyond the Helicobacter pylori-centric paradigm, the molecular-subtype-dependent duality of Fusobacterium nucleatum, the gut-liver axis, and the immunomodulatory potential of the intratumoral microbiome. We then examine how gut microbial communities shape ICI efficacy, tracing the field′s evolution from single-taxon association studies toward enterotype classification, multiomics integration, and function-based biomarkers that offer superior cross-cohort generalizability. The molecular mechanisms are analyzed through a spatiotemporal lens, encompassing the concentration-dependent dual immunoregulation by short-chain fatty acids, FXR/TGR5-mediated bile acid remodeling, tryptophan and other metabolite signaling, and molecular mimicry between microbial and tumor antigens. We further address the deleterious impact of antibiotic-induced dysbiosis, the microbiota-irAE relationship and its predictive value, and the immunological lessons drawn from microbial modulation of chemotherapy and radiotherapy, whose regulatory networks intersect extensively with those governing immunotherapy. Finally, we survey the emerging spectrum of precision microbial interventions—fecal microbiota transplantation, defined live biotherapeutic products, probiotics, prebiotics, postbiotics, and targeted microbiome editing via engineered probiotics, phage therapy, and CRISPR-based approaches—together with the critical, underexplored question of intervention timing and combinatorial sequencing. We propose that the predictive and therapeutic value of the microbiota lies not in isolated taxa but in integrated functional and metabolic networks, and that standardization of methodology, multi-omics and artificialintelligence-driven modeling, synthetic-biology-based ″minimal effective consortia″, and large-scale phase Ⅲ trials are prerequisites for clinical translation. Ultimately, we advocate a paradigm shift from a tumor-centric to a host-microbiotatumor ″triad″ model of systems microbial medicine, offering a new dimension for the precision treatment of GI cancers.

Communication Author：SHEN Lin , Email:shenlin@bjmu.edu.cn