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By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette\u2013Gu\u00e9rin therapy and who need to be treated with radical cystectomy, the new concept of \u201cbacillus Calmette\u2013Gu\u00e9rin unresponsive\u201d was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette\u2013Gu\u00e9rin\u2010unresponsive disease. A promising therapeutic strategy for bacillus Calmette\u2013Gu\u00e9rin\u2010unresponsive disease is the blockade of the programmed cell death\u20101\/programmed cell death\u2010ligand\u00a01 pathway, which is considered to be activated by bacillus Calmette\u2013Gu\u00e9rin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death\u20101\/programmed cell death\u2010ligand\u00a01 blockade in bacillus Calmette\u2013Gu\u00e9rin\u2010na\u00efve high\u2010risk non\u2010muscle\u2010invasive bladder cancer and bacillus Calmette\u2013Gu\u00e9rin\u2010unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette\u2013Gu\u00e9rin\u2010unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. 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