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Re-arming checkpoint blockade in MSS colorectal cancer: A precision-microbiome playbook from mechanisms to clinic
Zaid Safauldeen Ali Alsheikh1, Tao Qingsong1, Liu Qinjie1
1Department of General Surgery, Zhongda Hospital, Southeast University Faculty of Medicine, Nanjing, China.
Abstract:
Immune checkpoint blockade transforms outcomes for the 15% of colorectal cancers (CRCs) with mismatch-repair deficiency; yet most tumours remain refractory. Beneficial gut microbes can change this. Akkermansia muciniphila, Bacteroides fragilis, and short-chain fatty acid producers prime dendritic cells to produce interleukin (IL)-12, polarise Th1 cells, and reinvigorate CD8+ T-cells. Antibiotics, Western-style diets, and Fusobacterium nucleatum foster myeloid suppression and β-catenin- or IL-17-mediated signalling, which blunt checkpoint activity. Multi-omics analyses link biosynthetic genes for inosine, riboflavin, and folate to durable clinical benefit. Faecal microbiota transplantation from responders has produced objective regressions in otherwise refractory microsatellite-stable disease. This narrative review maps CRC-microbiota-immune crosstalk, evaluates biomarkers and interventions, and proposes a CRC-specific, three-tiered clinical algorithm. We outline standards for trial design and manufacturing processes to facilitate the translation of microbiota-guided therapy into routine practice.
Insights
Beneficial gut microbes can improve colorectal cancer (CRC) treatment response. Specific bacteria and their metabolites prime anti-tumour immunity, offering new therapeutic strategies for refractory microsatellite-stable CRC.
Area of Science:
- Oncology and Immunology
- Microbiome Research
- Gastroenterology
Background:
- Immune checkpoint blockade (ICB) benefits only 15% of colorectal cancers (CRCs) with mismatch-repair deficiency.
- Most CRCs remain refractory to ICB, necessitating novel therapeutic approaches.
- The gut microbiome significantly influences anti-tumour immunity and treatment efficacy.
Purpose of the Study:
- To review the intricate crosstalk between colorectal cancer, the gut microbiota, and the immune system.
- To evaluate potential biomarkers and therapeutic interventions targeting this interaction.
- To propose a clinical algorithm for microbiota-guided therapy in CRC.
Main Methods:
- Narrative review synthesizing current research on CRC-microbiota-immune interactions.
- Analysis of multi-omics data linking microbial metabolites to clinical benefit.
- Evaluation of faecal microbiota transplantation (FMT) studies in refractory CRC.
Main Results:
- Specific bacteria (e.g., Akkermansia muciniphila, Bacteroides fragilis) and short-chain fatty acid producers enhance anti-tumour immunity by priming dendritic cells and T-cells.
- Detrimental factors like antibiotics, Western diets, and Fusobacterium nucleatum promote immune suppression.
- Biosynthetic genes for inosine, riboflavin, and folate are associated with durable clinical benefit in CRC.
- FMT from responders has induced regressions in refractory microsatellite-stable CRC.
Conclusions:
- The gut microbiome plays a critical role in modulating CRC response to immunotherapy.
- Targeting microbial composition and function presents a promising avenue for enhancing ICB efficacy.
- Standardized approaches for microbiota-guided therapies are needed for clinical translation.
