Probiotic modulation of colorectal cancer stemness and metastasis: mechanisms and therapeutic implications

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, with metastasis, therapeutic resistance, and the persistence and plasticity of cancer stem cells (CSCs) contributing to treatment failure. This review evaluates evidence linking defined probiotic strains, multispecies formulations, and other microbiota-directed interventions to CRC stemness and metastatic biology. Because effects vary according to strain identity, viability, dose, formulation, host context, and experimental model, findings from one microorganism or product cannot be generalized across probiotics as a class. Most available studies do not demonstrate direct targeting of colorectal CSCs. Instead, reported effects are predominantly indirect and involve changes in microbiota composition, microbial metabolites, inflammatory and immune signaling, epithelial barrier integrity, and the tumor microenvironment. A smaller group of mechanistic studies identifies strain- and context-specific effects on stemness-related pathways. Animal studies also report effects on intestinal barrier integrity, tumor growth, angiogenesis, immune-cell composition, treatment-associated toxicity, and experimental treatment sensitivity, but these findings remain preclinical. Human evidence is limited and mainly concerns gastrointestinal symptoms, microbiota changes, and treatment tolerance. None of the human studies identified in this review demonstrated that probiotic supplementation improves objective tumor response, progression-free survival, overall survival, metastasis-free survival, or checkpoint-immunotherapy efficacy in CRC. Accordingly, the current literature supports biological plausibility for selected, well-characterized microbial interventions rather than a class-wide anticancer effect of probiotics. Direct CSC eradication, prevention of metastatic recurrence, and reproducible enhancement of chemotherapy/immunotherapy efficacy remain clinically unproven. Future studies require strain-resolved reporting, standardized dosing and formulation, mechanistic validation, and adequately powered clinical trials with oncologic endpoints.