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Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47 Page 11 of 17

attachment and invasion of Mycobacterium bovis successively [89,93] . The commensal microbes in the bladder
may impact the attachment and invasion of Mycobacterium bovis through colonization, metabolites or
interact with the immune cells, resulting in a synergistic or antagonistic effect on antitumor immunity.

Microbiota and immune checkpoint inhibition therapy
The immune checkpoint inhibition therapy (CPI) blocks immunosuppression induced by tumor cells
through competitively binding to receptors such as programmed cell death protein 1 (PD-1) and cytotoxic
T lymphocyte-associated protein 4 (CTLA-4) on immune cells, allowing tumor-infiltrating immune cells to
[94]
exert antitumor effects . The objective response rate (ORR) of immune checkpoint inhibitor monotherapy
in patients with metastatic bladder cancer who are intolerant to platinum-based chemotherapy is only 20%-
30% [95-97] .

Gut microbiota has been demonstrated to be associated with the efficacy of CPI in different cancers. For
instance, the gut microbiota is required for the antitumor effect of CTLA-4 blockade in melanoma and
[98]
colon cancer . Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species living in the
gut are proved to significantly enhance the efficacy of immune checkpoint inhibitors, including CTLA-4
and PD-1 inhibitors in bladder cancer, melanoma, and intestinal cancer murine models, which is dependent
on metabolite inosine . This prompts consideration of whether the urinary microbiota has a similar impact
[99]
on bladder cancer, but considering the gut microbiota constitutes the largest microbial reservoir in the
human body, it appears more plausible that local metabolic activity induced by urinary microbiota would
occur rather than systemic alteration induced by it. A clinical study found that the administration of
antibiotics attenuated the response to Pembrolizumab in NMIBC patients and was related to a lower rate of
[100]
complete response and recurrence-free survival , suggesting a prominent clinical impact of microbiota on
immunotherapy of bladder cancer. However, the role of urinary microbiota in the immunotherapy of
bladder cancer remains uncertain due to the potential perturbation of both urinary and gut microbiota by
various patterns of antibiotic metabolism. Furthermore, the gut microbiota has been shown to affect both
intestinal and extraintestinal cancers [98,99,101,102] , which makes it more complicated to identify whether gut
microbiota or urinary microbiota eliminated by antibiotics influences the efficacy of immunotherapy.
Characterization of the urinary microbiome has identified some bacteria that may be associated with CPIs
in bladder cancer. Chen et al. observed that Leptotrichia, Roseomonas, and Propionibacterium were enriched
in the urine of PD-L1-positive NMIBC patients, while Prevotella was enriched in PD-L1-negative patients,
[103]
suggesting that these bacteria genera may affect the responses of CPI . However, in fact, PD-L1 expression
in tumor or immune cells assessed by immunohistochemistry does not appear to be consistent with the
response to checkpoint inhibitors, and its use as a predictive marker is controversial . The association
[104]
between microbiota and antitumor immunity in bladder cancer requires additional investigation in
preclinical research.

Patients with metastatic bladder cancer have lost the chance to undergo surgery, leading to the selection of
systematic chemotherapy or immunotherapy as viable treatment options. Currently, treatment selection
cannot rely on predictive biomarkers as these biomarkers have not consistently differentiated patient groups
for treatment and are thus discouraged for clinical application .
[81]

Microbiota-based clinical interventions in bladder cancer
Microbiota represent complicated effects in cancer therapy. Removing carcinogenic bacteria like
Helicobacter pylori in the stomach has great significance in preventing gastric cancer, while the use of
antibiotics attenuates the therapeutic effect of CPI in melanoma. Up to now, microbiota is more of
therapeutic importance in bladder cancer. BCG intravesical instillation is broadly used as postoperative
follow-up treatment of bladder cancer, though it has many local and systemic side effects, such as bacterial