Improved tumor control with immune checkpoint blockade following metronidazole treatment

The gut microbiome influences tumor response to immune checkpoint blockade (ICB). Strategies to enrich favorable microbes, including fecal microbiota transplantation, can induce clinical responses to ICB in previously refractory patients. However, these approaches have limitations, necessitating novel and tractable methods to modulate the gut microbiome in patients with cancer. Here, we examined whether ICB response could be improved with the antibiotic metronidazole, which can impede growth of colorectal tumors through selective microbial depletion. A retrospective analysis of individuals treated with ICB at MD Anderson Cancer Center showed significantly improved survival among those treated with metronidazole prior to ICB, compared to individuals who received broad-spectrum (beta-lactam-based) antibiotics or no prior antibiotic exposure. These findings were validated in preclinical models, which revealed that metronidazole induced substantial increases in gut microbes and metabolic pathways previously linked with favorable ICB response, as well as enhanced cytotoxicity of tumor-infiltrating lymphocytes in combination with ICB. Our results have important implications for patients with cancer by providing a feasible strategy to modulate the gut microbiome, which could be applied immediately and globally to improve ICB response.