MMC lytic disruption of BCG unveils a hidden trap in bladder cancer combination immunotherapy

Bacillus Calmette-Guérin (BCG) is a core live bacterial agent for bladder cancer immunotherapy. To enhance its efficacy, chemotherapeutic drugs such as mitomycin C (MMC) are clinically used in combination with BCG. MMC acts by damaging tumor cell DNA to inhibit proliferation and induce cell death. For the first time, our experimental results demonstrate that MMC can directly lyse BCG, thereby impairing BCG’s antitumor functions, including its adhesion to and invasion of bladder tumor cells, as well as subsequent immune activation. In mouse models, MMC was shown to reduce the number of IFN-γ+CD4+ T cells induced by BCG. Furthermore, by adjusting the sequence of drug administration, the combined therapeutic effect was enhanced. The best outcome in our animal model was achieved when MMC was administered continuously prior to BCG. These findings may provide a reference for rational clinical drug use. As novel bacterial therapies for cancer are being actively explored, future live-bacterium treatments may face similar challenges when combined with conventional chemotherapy. This study may also offer insights into the rational application of future live-bacterial therapies in combination with chemotherapeutic agents.