Distinct Gut Microbiome and Metabolome Profiles Associate with Differential Responses to Immunotherapy in Colorectal Cancer
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Updated: Aug 7, 2026

Establishment of a Co-culture System of Patient-Derived Colorectal Tumor Organoids and Tumor-Infiltrating Lymphocytes (TILs)
Published on: June 27, 2025
Fang Liang1, Jing Li1,2,3, Yingkun Yue1
11Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
Abstract:
The composition of the intestinal microbiome has been identified as a key factor influencing the efficacy of immune checkpoint inhibitors. This study aimed to systematically evaluate the potential associations among gut microbiota, metabolic profiles, and clinical outcomes in patients with MSI-H advanced colorectal cancer (CRC) treated with immunotherapy. Twenty advanced CRC patients receiving immunotherapy were enrolled and categorized into clinical benefit response (CBR) and non-benefit (NCB) groups based on treatment efficacy. Fecal samples were analyzed using metagenomic sequencing and untargeted metabolomics. The results revealed significant enrichments of s_Clostridium unclassified and metabolites such as guanosine, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, and quercetin 3-(6"-malonyl-glucoside) in the CBR group, suggesting their potential positive predictive value for immunotherapy response. Conversely, the NCB group showed significant enrichments of s_Roseburia hominis, s_Marseilla massiliensis, and metabolites including pyrophosphate, riboflavin, and PC(22:5(4Z,7Z,10Z,13Z,16Z)/14:0), indicating a possible association with treatment resistance. By integrating fecal metagenomics and metabolomics, this study reveals distinctive "flora-metabolite" interactions linked to therapeutic response in advanced CRC patients undergoing immunotherapy. Specific microbial and metabolic profiles were positively or negatively correlated with immunotherapy outcomes, highlighting their potential not only as predictive biomarkers but also as a theoretical foundation for developing individualized immunotherapy strategies based on microecological modulation.
Insights
Gut microbiome and metabolites impact immunotherapy success in advanced colorectal cancer (CRC). Specific microbial and metabolic profiles predict response, offering potential for personalized treatment strategies.
Area of Science:
- Oncology
- Microbiome Research
- Immunotherapy
Background:
- Intestinal microbiome composition influences immune checkpoint inhibitor (ICI) efficacy.
- Understanding gut microbiota and metabolic profiles is crucial for optimizing immunotherapy in colorectal cancer (CRC).
Purpose of the Study:
- To investigate associations between gut microbiota, metabolic profiles, and clinical outcomes in advanced MSI-H CRC patients treated with immunotherapy.
- To identify potential predictive biomarkers for immunotherapy response in CRC.
Main Methods:
- Fecal metagenomic sequencing and untargeted metabolomics were performed on 20 advanced CRC patients undergoing immunotherapy.
- Patients were categorized into clinical benefit response (CBR) and non-benefit (NCB) groups based on treatment efficacy.
Main Results:
- The CBR group showed enrichment of 's_Clostridium unclassified' and specific metabolites (guanosine, quercetin derivative).
- The NCB group exhibited enrichment of 's_Roseburia hominis', 's_Marseilla massiliensis', and different metabolites (pyrophosphate, riboflavin).
- Distinct 'flora-metabolite' interactions correlated with immunotherapy outcomes were identified.
Conclusions:
- Specific gut microbial and metabolic profiles can serve as predictive biomarkers for immunotherapy response in advanced CRC.
- These findings provide a foundation for developing individualized immunotherapy strategies through microecological modulation.
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