From molecular networks to translational intervention: current progress in the mechanisms of gemcitabine resistance in bladder cancer.

Bladder cancer remains one of the most common malignancies of the urinary tract. Although the treatment landscape has expanded rapidly in recent years, gemcitabine still occupies a central position in intravesical treatment for non-muscle-invasive bladder cancer, in perioperative systemic therapy for muscle-invasive disease, and in platinum-based first-line regimens for advanced urothelial carcinoma. Yet the long-term benefit of gemcitabine is frequently curtailed by primary non-response or acquired resistance. In practice, this problem is often recognized only after radiographic progression or clear clinical deterioration has occurred. This review summarizes recent progress in bladder cancer therapy and translational research, with a particular emphasis on the biological basis and hierarchical evolution of gemcitabine resistance. We establish a 3-stage operational model of resistance, distinguishing: (1) early pharmacologic resistance driven by impaired drug uptake/activation or enhanced inactivation; (2) intermediate resistance driven by enhanced DNA damage repair, replication stress tolerance, and pro-survival autophagy signaling; and (3) late adaptive resistance driven by epithelial-mesenchymal transition (EMT), stemness maintenance, metabolic reprogramming, non-coding RNA-mediated epigenetic regulation, inflammatory microenvironmental remodeling, and extracellular vesicle-based intercellular transmission. These layers function as an interactive network, with sequential emergence under treatment pressure and parallel activation in context-dependent clinical settings. We stratify key mechanistic nodes (including the HYAL4-V1/CD44/JAK2-STAT3/CDA axis, AKR1C3, AP1M2-RAD54B, PRPF19-DDB1, AKT/mTOR signaling, Beclin-1-dependent autophagy, the MINCR/ZEB1/PHGDH axis, and IL-6-associated inflammatory states) by their clinical evidence quality and translational readiness, explicitly distinguishing preclinical discovery from clinically validated findings. Critically, most mechanistic findings remain at the preclinical or retrospective validation stage, with no markers yet approved for routine clinical use. Future work must prioritize longitudinal paired clinical samples, standardized analytic assays for dynamic biomarkers, and the integration of functional models (organoids, microfluidic systems), multi-omics technologies (single-cell sequencing, spatial transcriptomics), and liquid-biopsy approaches to translate mechanistic discoveries into clinically actionable predictive tools and therapeutic strategies.