BCG therapy in bladder cancer and its tumor microenvironment interactions

SUMMARY Bacillus Calmette-Guérin (BCG) has been the standard treatment for non-muscle-invasive bladder cancer for over 30 years. Despite its proven efficacy, challenges persist, including unclear mechanisms of action, resistance in 30%–50% of patients, and significant side effects. This review presents an updated and balanced discussion of the antitumor mechanisms of BCG, focusing on its direct effects on bladder cancer and its interactions with various cell types within the bladder tumor microenvironment. Notably, recent research on the interactions between BCG and the bladder microbiome is also incorporated. We further summarize and analyze the latest preclinical and clinical studies regarding both intrinsic and adaptive resistance to BCG in bladder cancer. Based on the current understanding of BCG’s therapeutic principles and resistance mechanisms, we systematically explore strategies to improve BCG-based tumor immunotherapy. These include the development of recombinant BCG, combination therapy with different drugs, optimization of therapeutic regimens and management, and the exploration of new approaches by targeting changes in the bladder microbiota and its metabolites. These measures aim to effectively address the BCG resistance in bladder cancer, reduce its toxicity, and ultimately enhance the clinical anti-tumor efficacy. Bacterial therapy, represented by genetically engineered oncolytic bacteria, has gradually emerged in the field of cancer treatment in recent years. As the only bacterial drug successfully approved for oncology use, BCG has provided decades of clinical experience. By consolidating lessons from BCG’s successes and limitations, we hope to provide valuable insights for the development and application of bacterial therapies in cancer treatment.