The study investigates the role of commensal bacteria in modulating the response to cancer therapy by influencing the tumor microenvironment. Disruption of the gut microbiota, through antibiotic treatment or germ-free conditions, impairs the effectiveness of CpG-oligonucleotide immunotherapy and platinum chemotherapy in subcutaneous tumors. In antibiotic-treated or germ-free mice, tumor-infiltrating myeloid-derived cells show reduced cytokine production, tumor necrosis, reactive oxygen species (ROS) production, and cytotoxicity compared to control mice. The findings suggest that an intact commensal microbiota is crucial for optimal responses to cancer therapy, as it mediates these effects by modulating the functions of myeloid-derived cells in the tumor microenvironment. The study also highlights the importance of the microbiota in the outcome of disease treatment, emphasizing the potential to improve cancer therapy by manipulating the gut microbiota.The study investigates the role of commensal bacteria in modulating the response to cancer therapy by influencing the tumor microenvironment. Disruption of the gut microbiota, through antibiotic treatment or germ-free conditions, impairs the effectiveness of CpG-oligonucleotide immunotherapy and platinum chemotherapy in subcutaneous tumors. In antibiotic-treated or germ-free mice, tumor-infiltrating myeloid-derived cells show reduced cytokine production, tumor necrosis, reactive oxygen species (ROS) production, and cytotoxicity compared to control mice. The findings suggest that an intact commensal microbiota is crucial for optimal responses to cancer therapy, as it mediates these effects by modulating the functions of myeloid-derived cells in the tumor microenvironment. The study also highlights the importance of the microbiota in the outcome of disease treatment, emphasizing the potential to improve cancer therapy by manipulating the gut microbiota.