• info@icbcongress.com
• English

ساخت اکانت کاربری رایگان

• ورود

INTERNATIONAL CONGRESS OF

CancerGenetics

• The Role of the Gut Microbiome and Microbial Metabolites in Modulating Responses to Immune Checkpoint Inhibitors (ICIs): A Review of Immunological Mechanisms, Clinical Evidence and Microbiome-Based Therapeutic Strategies

• Alireza Nikkhah,^1,* Mohammad Hashemabadi,² Abbas Hajizade,³
  1. Biology Research Center, Faculty of Basic Sciences , Imam Hossein University Tehran, Iran
  2. Department of Cellular and Molecular Biology, Faculty of Life science and Biotechnology, Shahid beheshti university, Tehran, Iran
  3. Biology Research Center, Faculty of Basic Sciences , Imam Hossein University Tehran, Iran
  
  
  
• Introduction: Immune checkpoint inhibitors (ICIs), particularly antibodies targeting programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have substantially transformed cancer treatment. However, only a proportion of patients achieve durable clinical benefit, while primary and acquired resistance remain major therapeutic challenges. Although established biomarkers such as PD-L1 expression, tumor mutational burden, and deficient mismatch repair/microsatellite instability provide clinically useful information in selected settings, they do not fully explain the heterogeneity of responses to immunotherapy. Increasing evidence suggests that the gut microbiome represents an additional and potentially modifiable component of the gut–immune–tumor axis. This review summarizes current evidence regarding the immunological mechanisms, microbial metabolites, clinical microbial signatures, and therapeutic strategies linking the gut microbiome to ICI efficacy.
• Methods: This narrative review was developed to integrate evidence on the role of the gut microbiota and microbial metabolites in modulating responses to ICIs. Relevant literature published between 2018 and 2026 was examined using PubMed/MEDLINE, Scopus, and Web of Science. The search strategy incorporated combinations of terms related to the gut microbiome, cancer immunotherapy, immune checkpoint inhibitors, microbial metabolites, treatment resistance, fecal microbiota transplantation (FMT), and microbiome-based interventions. Evidence from basic, preclinical, translational, and clinical studies was considered to characterize interactions between microbial communities, host immunity, tumor biology, and therapeutic response.
• Results: The reviewed evidence indicates that the gut microbiome can influence antitumor immunity through several interconnected mechanisms. Microbe-associated molecular patterns can stimulate pattern-recognition receptors and promote antigen-presenting cell activation, cytokine production, and subsequent T-cell responses. In addition, microbial antigens may share epitopes with tumor-associated antigens, potentially contributing to cross-reactive T-cell responses. Experimental evidence has demonstrated molecular cross-reactivity between tumor MHC class I-restricted antigens and microbial bacteriophage-associated antigens, supporting a potential role for microbial antigen exposure in antitumor immunity.Microbial metabolites represent another important functional interface between the microbiome and the immune system. Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, can influence immune-cell function through G-protein-coupled receptors and epigenetic mechanisms. Preclinical studies have shown that butyrate can enhance cytotoxic CD8+ T-cell activity through mechanisms involving ID2 and IL-12 signaling, although the strongest mechanistic evidence is not restricted to ICI therapy and includes other anticancer treatments. Microbiome-derived inosine has also been shown to modulate checkpoint inhibitor responses in preclinical models through adenosine A2A receptor-dependent pathways. Tryptophan-derived metabolites and secondary bile acids may further influence immune homeostasis through pathways involving the aryl hydrocarbon receptor and other metabolite-sensitive signaling systems.Clinical studies have demonstrated associations between gut microbial composition and ICI outcomes, although these associations vary according to cancer type, treatment regimen, population, and analytical approach. Increased microbial diversity and enrichment of specific taxa, including Akkermansia muciniphila and members of the Ruminococcaceae and Lachnospiraceae families, have been associated with favorable responses in selected patient cohorts. Importantly, recent strain-level and metagenomic studies suggest that microbial signatures may be more informative when microbial functions, metabolic characteristics, and treatment context are considered rather than relying solely on individual bacterial species. Antibiotic exposure has also been associated with poorer outcomes in several studies, supporting the potential importance of microbiome disruption during immunotherapy, although these observational findings do not establish causality.Interventional studies provide early evidence that the microbiome may be therapeutically modifiable. FMT combined with anti-PD-1 therapy has produced responses in subsets of patients with melanoma resistant to previous immunotherapy, accompanied by changes in immune and tumor-microenvironment features. Dietary factors, particularly fiber intake, have also been associated with immunotherapy outcomes, while preclinical evidence suggests that dietary and probiotic interventions can alter treatment efficacy. Nevertheless, FMT, live biotherapeutic products, dietary interventions, and defined microbial consortia remain investigational and require further validation.
• Conclusion: The gut microbiome and its metabolic products constitute important components of the biological network regulating responses to immune checkpoint blockade. Current evidence supports multiple mechanisms involving antigen presentation, immune-cell activation, microbial antigen cross-reactivity, and metabolite-mediated signaling. However, no single microbial species or signature can currently predict ICI response across all cancer types and treatment regimens. Biological heterogeneity, geographical and dietary differences, host factors, antibiotic exposure, sampling variability, and differences in microbiome profiling methods remain major barriers to clinical translation. Future research should therefore move beyond single-species biomarkers toward functional and multi-layered signatures integrating metagenomics, metabolomics, immune profiles, and tumor characteristics. Standardized sampling and analytical approaches, independent validation, and multimodal computational models may facilitate the development of more robust microbiome-based biomarkers and therapeutic strategies for precision oncology.
• Keywords: Gut Microbiome ,Immune Checkpoint Inhibitors (ICIs) , Cancer Immunotherapy, Precision Oncology