Modulation of the response to immunotherapy in triple-negative breast cancer: the role of the microbiota and microbial metabolites in the tumor microenvironment

Triple-negative breast cancer is an aggressive and heterogeneous breast cancer subtype for which immune checkpoint inhibitors combined with chemotherapy have improved outcomes in selected patients. However, primary and acquired resistance remain common, underscoring the need to identify extrinsic, modifiable determinants of antitumor immunity. Increasing evidence indicates that the gut and tumor-associated microbiota shape systemic and intratumoral immune tone and influence the efficacy of cancer therapies. Beyond microbial composition, microbiota-derived metabolites-including short-chain fatty acids, indole-tryptophan derivatives, bile acids, polyamines, and other small molecules-can act as functional mediators linking microbial ecology to immune-cell programming and tumor biology. These metabolites modulate dendritic cell function, T-cell priming and fitness, myeloid polarization, inflammatory set points, and metabolic pathways within the tumor microenvironment, thereby potentially enhancing or constraining responses to chemoimmunotherapy. Importantly, while some studies propose intratumoral microbial effects, most clinically actionable evidence currently supports systemic gut-derived metabolites and immune tone modulation that secondarily shapes the TNBC tumor microenvironment. In this review, we synthesize current knowledge on (i) the immunobiology of triple-negative breast cancer (TNBC) relevant to microbiota-driven modulation, (ii) mammary and gut microbiome features reported in TNBC, and (iii) mechanistic pathways through which microbial metabolites may regulate antitumor immunity and immune checkpoint inhibitors (ICI) sensitivity. We also discuss methodological considerations for integrating microbiome profiling with metabolomics and immune phenotyping and evaluate emerging opportunities to leverage microbiota-derived metabolites as biomarkers and therapeutic targets. Finally, we highlight translational strategies-including diet, pre/probiotics, antibiotic stewardship, fecal microbiota transplantation, and metabolite-centric ("postbiotic") approaches-and outline priorities for TNBC-focused, prospective multi-omics studies to move from associative signatures toward actionable interventions.