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.卡介苗（Bacillus Calmette-Guérin, BCG）是膀胱癌免疫治疗的核心活菌制剂。临床中常将丝裂霉素C（mitomycin C, MMC）等化疗药物与卡介苗联合使用，以提升其治疗效果。丝裂霉素C通过损伤肿瘤细胞DNA，抑制肿瘤细胞增殖并诱导细胞死亡。本研究首次通过实验结果证实，丝裂霉素C可直接裂解卡介苗，进而削弱卡介苗的抗肿瘤功能，包括其对膀胱肿瘤细胞的黏附与侵袭能力，以及后续的免疫激活效应。在小鼠模型中，丝裂霉素C可减少卡介苗诱导产生的IFN-γ⁺CD4⁺ T细胞数量。此外，通过调整给药顺序可增强联合治疗效果：本动物模型的最佳联合方案为在卡介苗给药前持续给予丝裂霉素C。上述研究结果可为临床合理用药提供参考。随着新型肿瘤细菌疗法的研究日益活跃，未来活菌疗法与传统化疗药物联用时或面临类似挑战。本研究也可为未来活菌疗法与化疗药物的合理联用提供思路。