The gut-tumor metabolic axis: A comprehensive exploration of bidirectional crosstalk in cancer immunotherapy
Recommended Citation
Kawuribi V, Awere-Duodu A, Adjei FA, Osman AH, Bomansaan H, Madadi MM, Tampuri JU, Adu-Amankwaah J. The gut-tumor metabolic axis: A comprehensive exploration of bidirectional crosstalk in cancer immunotherapy. Crit Rev Oncol Hematol. 2026;222:105280.
Document Type
Article
Publication Date
6-1-2026
Publication Title
Critical reviews in oncology/hematology
Keywords
Humans, Neoplasms, Immunotherapy, Gastrointestinal Microbiome, Animals, Tumor Microenvironment
Abstract
The gut-tumor metabolic axis represents a bidirectional immunometabolic network in which tumor-derived metabolites reshape microbial ecology, while gut microbiome-derived metabolites recalibrate systemic and intratumoral immunity, ultimately influencing cancer progression and immunotherapy outcomes. Tumor aerobic glycolysis generates excess lactate and acidity that suppress cytotoxic immune function, remodel the tumor immune microenvironment, and indirectly perturb intestinal microbial composition. In turn, microbial metabolites including short-chain fatty acids, bile acid derivatives, tryptophan catabolites, inosine, and trimethylamine N-oxide signal through defined host pathways such as GPR109A, AHR, and adenosine A2A receptors to regulate antigen presentation, T-cell differentiation, macrophage polarization, and immune checkpoint sensitivity. Preclinical and emerging clinical evidence demonstrates that dietary modulation, rational probiotics, and fecal microbiota transplantation can enhance immune checkpoint inhibitor efficacy in selected contexts. However, metabolite effects are highly context dependent, with dose, timing, tumor type, and immune state critically shaping therapeutic benefit or resistance. This review integrates mechanistic insights and clinical evidence, highlights translational challenges including safety, donor heterogeneity, and biomarker validation, and proposes a framework for biomarker-guided microbiome-based strategies to advance precision cancer immunotherapy.
Medical Subject Headings
Humans; Neoplasms; Immunotherapy; Gastrointestinal Microbiome; Animals; Tumor Microenvironment
PubMed ID
41839398
Volume
222
First Page
105280
Last Page
105280
