Microbiome-Based Therapeutics in Oncology: Expanding Indications Beyond C. difficile

The intestinal microbiome has emerged as a clinically significant modulator of outcomes across multiple domains of cancer care. In hematopoietic stem cell transplantation (HSCT), loss of microbial diversity and depletion of short-chain fatty acid–producing commensals are independently associated with graft-versus-host disease (GvHD), bloodstream infections, transplant-related mortality, and overall survival. Mechanistic studies have identified interconnected pathways — including butyrate-mediated epithelial protection, tryptophan-derived aryl hydrocarbon receptor signaling, bile acid metabolism, and Paneth cell–intestinal stem cell interactions — through which microbial communities regulate intestinal barrier integrity and immune homeostasis. These insights have provided the biological rationale for therapeutic strategies aimed at restoring microbial ecology. Fecal microbiota transplantation (FMT) has demonstrated promising clinical activity in steroid-refractory acute GvHD, with pooled remission rates exceeding 60% in meta-analyses, and proprietary live biotherapeutic products (LBPs) such as MaaT013 have advanced to phase III testing. In parallel, the gut microbiome has been established as a determinant of immune checkpoint inhibitor (ICI) efficacy, with FMT shown to overcome anti-PD-1 resistance in refractory melanoma and enhance response rates in treatment-naive patients with melanoma and non-small cell lung cancer. Defined single-strain approaches, notably Clostridium butyricum CBM588, have demonstrated significant improvements in progression-free survival when combined with ICI in metastatic renal cell carcinoma. Emerging evidence further links antibiotic-induced dysbiosis to impaired chimeric antigen receptor T-cell (CAR-T) therapy outcomes, while short-chain fatty acids have been identified as direct enhancers of CAR-T cell effector function. This review synthesizes the current evidence for microbiome-based therapeutics across HSCT, GvHD, ICI therapy, CAR-T cell therapy, and infection prevention, and addresses cross-cutting translational challenges including antibiotic stewardship, donor selection, safety in immunocompromised populations, and pharmacomicrobiomics. While randomized controlled trial data remain limited and many approaches are investigational, the convergence of mechanistic, observational, and early interventional evidence positions microbiome restoration as a promising frontier in precision oncology.