An Intravesical Akkermansia muciniphila ‐Based Chemo‐Immunotherapeutic Platform for Bladder Cancer

ABSTRACT

Bladder cancer (BC) is a highly recurrent urinary malignancy for which current intravesical immunotherapy and chemotherapy are limited by insufficient efficacy, toxicity, excessive inflammation, and drug resistance. The probiotic Akkermansia muciniphila (AKK), known for its ability to modulate immune responses and suppress pathological inflammation, provides a promising immunomodulatory component to address these limitations. Here, an intravesical bacteria‐based chemo‐immunotherapeutic platform is developed by loading doxorubicin (DOX) onto pasteurized AKK modified with F127, yielding AKK‐F127/DOX (AF/D). Compared with free DOX, AF/D more effectively inhibits bladder cancer cell proliferation, migration, and invasion, while inducing apoptosis, ferroptosis, immunogenic cell death, and suppressing the NF‐κB inflammatory pathway. AF/D also promotes dendritic‐cell maturation, pro‐inflammatory cytokine secretion, M1‐like macrophage polarization, antigen cross‐presentation, and tumor‐specific CD8 ⁺ T‐cell priming. In orthotopic bladder cancer models, intravesical AF/D shows superior antitumor efficacy and survival benefits over single‐agent treatments, remodels the local immune microenvironment, enhances systemic antigen‐specific CD8 ⁺ T‐cell responses in the spleen, and maintains a favorable safety profile. These findings establish AF/D as a promising intravesical chemo‐immunotherapeutic strategy for bladder cancer.