Extracellular vesicles as integrative hubs of drug resistance in bladder cancer

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Abstract
Therapeutic resistance remains a major challenge in bladder cancer, encompassing resistance to intravesical Bacillus Calmette–Guérin (BCG) therapy, platinum- and gemcitabine-based chemotherapy and immune-checkpoint blockade. Although extracellular vesicles (EVs) have been implicated in cancer drug resistance, their roles in bladder cancer are often discussed within the broader context of EV biology, making it difficult to distinguish direct mechanisms of treatment resistance from treatment-associated remodelling or biomarker associations. In this review, we refocus EV-mediated therapeutic resistance in bladder cancer and propose an evidence-stratified framework, distinguishing EVs as causal mediators, permissive amplifiers or biomarkers of drug adaptation. Studies have provided substantial mechanistic evidence from chemotherapy-associated models, including EV-mediated regulation of gemcitabine resistance through H3C14-associated EV remodelling and chemotherapy-exposed bladder cancer EVs that support stem-like, treatment-tolerant tumour states. Evidence supporting EV involvement in platinum resistance, BCG failure and immunotherapy resistance remains biologically plausible but less directly established. Therefore, clearer drug-specific models, improved EV-subtype resolution, cargo perturbation and functional rescue experiments are needed. We also discuss urinary EVs for longitudinal monitoring of treatment response and emerging resistance in bladder cancer. By integrating drug-specific therapeutic contexts with EV-specific causality criteria, this review provides a focused framework for evaluating when EVs mediate bladder cancer drug resistance, amplify adaptive tumour–microenvironment states or primarily serve as biomarkers for therapeutic monitoring.

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