---
title: "Tumor Microenvironment and Gut Microbiome in Immunotherapy Resistance in Gastric Cancer"
id: "pubmed-42848247"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42848247"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42848247/"
doi: "10.1007/s12032-026-03434-z"
published_at: "2026-10-08T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tumor Microenvironment and Gut Microbiome in Immunotherapy Resistance in Gastric Cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42848247
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42848247/)
- **DOI:** [10.1007/s12032-026-03434-z](https://doi.org/10.1007%2Fs12032-026-03434-z)
- **Published At:** 2026-10-08T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Immune checkpoint inhibitors (ICIs) have improved systemic therapy for advanced **gastric cancer** and gastroesophageal junction cancer, but **primary and acquired resistance** are still common and not fully explained by established tumor biomarkers. - This narrative review assessed the interplay among the **tumor microenvironment (TME)**, host immunity, and the **gut microbiome** as contributors to ICI resistance in gastric cancer, using a structured PubMed search through 28 August 2026. - Within the gastric cancer TME, features that can promote immune exclusion or dysfunction include **cancer-associated fibroblasts**, myeloid cell populations, **regulatory T cells**, extracellular matrix remodeling, hypoxia, angiogenesis, and **T-cell exhaustion**. - The gut microbiome may influence systemic antitumor immunity through microbial diversity, microbial metabolites, prior **antibiotic** exposure, **proton pump inhibitor (PPI)** use, defined live biotherapeutics, **fecal microbiota transplantation (FMT)**, and **diet**, but most human evidence is retrospective, cross-sectional, or derived from non-gastric cancers. - Clinically reasonable supportive measures suggested by current evidence include **antibiotic stewardship**, reassessment of unnecessary acid suppression, and **nutritional optimization** for patients on ICIs. - Routine probiotic supplementation, use of **Clostridium butyricum MIYAIRI 588** to sensitize ICIs, and **FMT** remain investigational specifically in gastric cancer according to the review. - The authors recommend that future studies integrate longitudinal exposure data, serial TME profiling, stool metagenomics, medication use, nutritional status, and clinical outcomes to better define the **TME–gut microbiome axis** as a biomarker-guided research framework. - Current evidence supports biological plausibility for microbiome–TME interactions in ICI resistance but does not justify empiric microbiome-directed anticancer therapy in gastric cancer at this time.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan. stamotsu@jk9.so-net.ne.jp. * 2 Division of Medical Oncology, Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. * 3 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan. * PMID: **42848247** * DOI: [ 10.1007/s12032-026-03434-z ](https://doi.org/10.1007/s12032-026-03434-z) Item in Clipboard Review # Tumor microenvironment and gut microbiome in immunotherapy resistance in gastric cancer: clinical questions, biological mechanisms, and evidence-based therapeutic perspectives Tamotsu Sagawa et al. Med Oncol. 2026. Show details Display options Display options Format Abstract PubMed PMID Med Oncol Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Med+Oncol%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Med+Oncol%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) . 2026 Oct 8;43(11):308. doi: 10.1007/s12032-026-03434-z. ### Authors [Tamotsu Sagawa](https://pubmed.ncbi.nlm.nih.gov/?term=Sagawa+T&cauthor_id=42848247)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42848247/#short-view-affiliation-1 "Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan. stamotsu@jk9.so-net.ne.jp."), [Masahiro Hirakawa](https://pubmed.ncbi.nlm.nih.gov/?term=Hirakawa+M&cauthor_id=42848247)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42848247/#short-view-affiliation-2 "Division of Medical Oncology, Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan."), [Hiroyuki Nagashima](https://pubmed.ncbi.nlm.nih.gov/?term=Nagashima+H&cauthor_id=42848247)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42848247/#short-view-affiliation-3 "Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan."), [Koshi Fujikawa](https://pubmed.ncbi.nlm.nih.gov/?term=Fujikawa+K&cauthor_id=42848247)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42848247/#short-view-affiliation-3 "Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan.") ### Affiliations * 1 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan. stamotsu@jk9.so-net.ne.jp. * 2 Division of Medical Oncology, Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. * 3 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan. * PMID: **42848247** * DOI: [ 10.1007/s12032-026-03434-z ](https://doi.org/10.1007/s12032-026-03434-z) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Immune checkpoint inhibitors (ICIs) have improved systemic therapy for advanced gastric and gastroesophageal junction cancer, yet primary and acquired resistance remain common and are incompletely explained by established tumor biomarkers. This narrative review evaluates the connected roles of the tumor microenvironment (TME), host immunity, and the gut microbiome in shaping ICI resistance in gastric cancer. We performed a structured PubMed search through 28 August 2026 and prioritized gastric cancer-specific clinical and translational evidence, supplemented by systematic reviews, meta-analyses, and mechanistically relevant studies from other tumor types when necessary. Within the gastric cancer TME, cancer-associated fibroblasts, myeloid cells, regulatory T cells, extracellular matrix remodeling, hypoxia, angiogenesis, and T-cell exhaustion can promote immune exclusion or dysfunction. Microbial diversity, microbial metabolites, antibiotics, proton pump inhibitors, defined live biotherapeutics, fecal microbiota transplantation, and diet may influence systemic antitumor immunity, but most human evidence is retrospective, cross-sectional, or derived from non-gastric cancers. Clinically, antibiotic stewardship, reassessment of unnecessary acid suppression, and nutritional optimization are reasonable supportive measures, whereas routine probiotic supplementation, Clostridium butyricum MIYAIRI 588 for ICI sensitization, and fecal microbiota transplantation remain investigational in gastric cancer. Future studies should integrate longitudinal exposures, serial TME profiling, stool metagenomics, medication use, nutritional status, and clinical outcomes. The TME-gut microbiome axis is therefore a biologically plausible framework for biomarker-guided research, but current evidence does not justify empiric microbiome-directed anticancer therapy in gastric cancer. **Keywords:** Gastric cancer; Gut microbiome; Immune checkpoint inhibitor; Immunotherapy resistance; Microbiome modulation; Tumor microenvironment. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Competing interests: The authors declare no competing interests. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent to publish: Not applicable. ## References 1. 1. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40. . - [DOI](https://doi.org/10.1016/s0140-6736\(21\)00797-2) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/34102137/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/8436782/) 2. 1. Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:234–47. . - [DOI](https://doi.org/10.1016/s1470-2045\(21\)00692-6) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/35030335/) 3. 1. Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1181–95. . - [DOI](https://doi.org/10.1016/s1470-2045\(23\)00515-6) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/37875143/) 4. 1. Kieffer Y, Hocine HR, Gentric G, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020;10:1330–51. . - [DOI](https://doi.org/10.1158/2159-8290.cd-19-1384) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/32434947/) 5. 1. Liu T, Han C, Wang S, et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019;12:86. . - [DOI](https://doi.org/10.1186/s13045-019-0770-1) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/31462327/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/6714445/) Show all 42 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) ## MeSH terms * Drug Resistance, Neoplasm* / immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Drug+Resistance%2C+Neoplasm%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Drug+Resistance%2C+Neoplasm) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Gastrointestinal Microbiome* / drug effects Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Gastrointestinal+Microbiome%2Fdrug+effects%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Gastrointestinal+Microbiome) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Gastrointestinal Microbiome* / immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Gastrointestinal+Microbiome%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Gastrointestinal+Microbiome) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Humans Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Humans) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Immune Checkpoint Inhibitors* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immune+Checkpoint+Inhibitors%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Immune+Checkpoint+Inhibitors) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Immune Checkpoint Inhibitors* / therapeutic use Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immune+Checkpoint+Inhibitors%2Ftherapeutic+use%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Immune+Checkpoint+Inhibitors) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Immunotherapy* / methods Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immunotherapy%2Fmethods%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Immunotherapy) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Stomach Neoplasms* / drug therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Stomach+Neoplasms%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Stomach+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Stomach Neoplasms* / immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Stomach+Neoplasms%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Stomach+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Stomach Neoplasms* / microbiology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Stomach+Neoplasms%2Fmicrobiology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Stomach+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Stomach Neoplasms* / pathology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Stomach+Neoplasms%2Fpathology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Stomach+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42848247/) * Stomach Neoplasms* / therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Stomach+Neoplasms%2Ftherapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Stomach+Neoplasms) * [ Add to
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